Ib-o-alkyl-deserkdates and related



United States Patent 3,126,388 IS-O-ALKYL-DESERPKDATES AND RELATED COMPOUNDS Michael Mullen Robison, Berkeley Heights, and Robert Armisteatl Lucas, Mendharn, Ni, assignors to Ciba Corporation, a corporation of Delaware No Drawing. Filed May 16, 1961, Ser. No. 110,321 23 Claims. (Cl. 260-287) The present invention concerns 3-epi-allo-yohimbane compounds having the nucleus of the formula:

More particularly, it relates to 18-etherified hydroxy-B- epi-allo-yohimbane 16B-carboxylic acid esters, particularly IS-etherified hydroxy-l7a-R-3-epi-allo-yohimbane 16fi-carboxylic acid esters, in which R represents primarily lower alkoxy, as well as cyano, salts, N-oxides or salts of N-oxides of such compounds. Apart from the groups attached to the 16-position, the 17-position and the 18-position, the compounds of the present invention may contain additional substituents. Thus, substituents attached to the positions of the aromatic nucleus, i.e. ring A, of the molecule, more specifically to the 9-position, the lo-position, the ll-position and/or the l2-position, are represented, for example, by aliphatic hydrocarbon, such as lower alkyl and the like, etherified hydroxyl, particularly lower alkoxy, as well as cycloalkyloxy, cycloalkyl-lower alkoxy, carbocyclic aryloxy, carbocyclic aryl-lower alkoxy, lower alkylenedioxy and the like, esterified hydroxyl, particularly halogeno, as well as lower alkoxy-carbonyloxy, lower alkanoyloxy and the like, etherified mercapto, such as lower alkylmercapto and the like, nitro, amino, such as N,N-disubstituted amino and the like, substituted aliphatic hydrocarbon, such as substituted lower alkyl, for example, halogeno lower alkyl, particularly trifluoromethyl, or any other suitable substituent. Other substituents, particularly aliphatic hydrocarbon radicals, such as lower alkyl, may also be attached to positions of other nuclei, particularly of the heterocyclic nucleus C, more specifically to the -position and/ or the 6-position.

More especially, the invention is directed to compounds of the formula:

lower alkyl, as well as a substituted aliphatic radical,

3,126,388 Patented Mar. 24, 1964:

primarily substituted lower alkyl, such as, for example, monocyclic carbocyclic aryl-lower alkyl, e.g. phenyllower alkyl and the like, etherified hydroXy-lower alkyl, e.g. lower alkoXy-lower alkyl and the like, tertiary aminolower alkyl, e.g. bLN-di-lower alkyl-amino-lower alkyl and the like, R stands primarily for lower alkoxy, as well as for cyano, R represents an aliphatic radical, prirnmily lower alkyl, as well as lower alkenyl, lower alkynyl and the like, including a cycloaliphatic radical, such as cycloalkyl or cycloalkenyl, or a substituted aliphatic radical, particularly substituted lower alkyl, which is substituted, for example, by a cycloaliphatic radical, such as cycloalkyl or cycloalkenyl, carbocyclic aryl, such as monocyclic carbocyclic aryl and the like, hydroxyl, etherified hydroxyl, especially lower alkoxy and the like, esterified hydroxyl, such as lower alkoxy-carbonyloxy, lower alkanoyloxy, carbocyclic aryl-carbonyloxy, carbocyclic aryl-lower aliphatic hydrocarbon-carbonyloxy, halogeno and the like, acyl, such as lower alkanoyl, carbo-lower alkoxy and the like, mercapto, etherified mercapto, such as lower alkyl-mercapto and the like, tertiary amino, for example, N,N-di-lower alkyl-amino and the like, a heterocyclic, particularly a monocyclic heterocyclic, radical, or any other analogous group suitable for being attached to an aliphatic radical, each of the radicals R R and R stands for hydrogen, aliphatic hydrocarbon, particularly lower alkyl and the like, substituted aliphatic hydrocarbon, particularly substituted lower alkyl, such as halogeno-lower alkyl, especially trifluoromethyl, etherified hydroxyl, particularly lower alkoxy, as Well as cycloalkyloxy, cycloalkyl-lower alkoxy, carbocyclic aryloxy, carbocyclic aryl-lower alkoxy or any other analogous etherified hydroxy group, esterified hydroxyl, particularly halogeno, as well as lower alkoxycarbonyloxy, lower alkanoyloxy and the like, etherified mercapto, particularly lower alkyl -mercapto, nitro, amino, e.g. N,Ndi-substituted amino and the like, or, whenever two of the groups R R and R are attached to two adjacent positions and are taken together, for

lower alkylenedioxy, and R attached to one of the positions 5 and 6, stands for hydrogen or lower alkyl, salts, N-oxides or salts of N-oxidbs of such compounds, as well as process for the preparation of such compounds.

The invention is also directed to compounds of the formula:

n -c-c o r B which, in the above formulae, is represented by the group R stands above all for lower alkyl containing from one to ten, preferably from one to four, carbon atoms; such '1, groups are particularly methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl and the like, as well as n-pentyl, isopentyl, n-hexyl, n-heptyl and the like.

The esterifying portion of the ester grouping attached to the l6fl-position of the molecule, represented, for example, by the radical R in the above formulae, may also stand for substituted aliphatic, particularly substituted lower alkyl, radicals, such as, for example, monocyclic carbocyclic aryl-lower alkyl, in which lower alkyl contains from one to four carbon atoms, such as phenyllower alkyl, e.g. benzyl, l-phenyl-ethyl, 2-phenylethyl and the like, or phenyl-lower alkyl, in which phenyl is substituted by lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, halogeno, e.g. fiuoro, chloro, bromo and the like, or any other suitable substituent.

Other substituted aliphatic, particularly lower alkyl, radicals, as represented, for example, by the group R in the above formulae, are aliphatic, especially lower alkyl, radicals substituted by functional groups, such as etherificd hydroxyl, particularly lower alkoxy containing preferably from one to four carbon atoms, e.g. methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy and the like, tertiary amino, particularly N,N-di-lower alkylamino, in which lower alkyl contains from one to four carbon atoms, e.g. N,N dimethylamino, N ethyl N methylamino, N,N-diethylamino, N,N-di-n-propylamino, N,N-di-isopropylamino and the like, as well as l-N,N- alkylene-imino, in which alkylene contains from four to six ring carbon atoms, e.g. 1-pyrrolidino, l-piperidino, 1-N,N-hexamethyleneimino and the like, 1-N,N-oxa-alkylene-imino, in which oxa-alkylene contains preferably four ring carbon atoms, e.g. 4-morpholino and the like, N,N-thia-alkylene-imino, in which alkylene contains preferably four carbon atoms, e.g. l-thiamorpholino and the like, or l-N,N-aza-alkylene-imino, in which aza-alkylene contains from four to six ring carbon atoms, particularly 4-lower alkyl-l-piperazino, e.g. 4-methyl-l-piperazino, 4- ethyl-l-piperazino and the like. The aliphatic, particularly the lower alkyl, portion in an aliphatic, especially lower alkyl, radical substituted by functional groups, such as in an etherified hydroxy-lower alkyl radical, or in a tertiary amino-lower alkyl radical and the like, may be represented by a lower alkylene radical, which contains at least two, preferably from two to three, carbon atoms, separating the functional group, such as etherified hydroxyl, tertiary amino and the like, from the 16/8-carboxyl group in the molecule by at least two, preferably by from two to three, carbon atoms. Such alkylene radicals are primarily 1,2-ethylene, 1-methyl-1,2-ethylene, 2- methyl-1,2-ethylene, 1,3-propylene, as well as l,4-butylene and the like. Aliphatic, particularly lower alkyl radicals containing functional groups, which radicals are rep resented by R in the above formulae, may be primarily lower alkoxy-lower alkyl, in which lower alkyl has from two to three carbon atoms and separates the lower alkoxy group from the 16B-carboxyl group in the molecule by at least two carbon atoms, for example, 2-lower alkoxyethyl, e.g. Z-methoxyethyl, Z-ethoxyethyl and the like, 2-lower alkoxy-propyl, e.g. Z-methoxy-propyl and the like, 3-1ower alkoxy-propyl, e.g. methoxypropyl, 3-ethoxypropyl and the like. Other substituted aliphatic, particularly lower alkyl radicals, are, for example, N,N-dilower alkyl-aminodower alkyl, in which lower alkyl carrying the N,N-di-lower alkyl-amino group has from two to three carbon atoms and separates the N,N-di-lower alkyl-amino group from the 16,8-carboxyl group in the molecule by at least two carbon atoms, for example, 2- N,N-di-lower alkyl-ethyl, e.g. 2-N,N-dimethy1aminoethyl, 2-N,N-diethylaminoethyl and the like, 2-N,N-di-lower alkyl-amino-propyl, e.g. 2-N,N-diethylaminopropyl and the like, 3-N,N-di-lower alkyl-amino-propyl, e.g. 3-N,N- dimethylaminopropyl, 3-N,N-diethylaminopropyl and the like, N,N-alkylene-imino-lower alkyl, in which lower alkyl has from two to three carbon atoms and separates the N,N-alkylene-irnino group from the 16 3-carboxyl group in the molecule by at least two carbon atoms, and alkylene contains from four to seven carbon atoms, such as 2-(1- N,N-alkylene-imino)-ethyl, e.g. 2-( l-pyrrolidino)-ethyl, 2-(1-piperidino)-ethyl and the like, 2-(l-N,N-alkyleneimino)-propyl, e.g. 2-(1-pyrrolidino)-propyl, 2-(1-piperidino)-propyl and the like, 3-( l-N,N-alkylene-imino)- propyl, e.g. 3-(1-piperidino)-propyl, 3-(l-N,N-hexamethylene-imino)-propyl and the like, or any other suitable tertiary amino-lower alkyl radical.

The substituent attached to the t-POSltlOn, as represented by the group R in the above formulae, represents lower alkoxy which contains preferably from one to four carbon atoms, and stands primarily for methoxy, as well as ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy and the like. It may also stand for cyano.

The etherified hydroxyl group attached to the 18-p0sition and represented, for example, by the grouping R O- in the previously given formulae, is etherified by an aliphatic radical including a cycloaliphatic or a substituted aliphatic radical. These radicals, represented in the above formulae by the group R stand, above all, for lower alkyl, containing from one to ten, preferably from one to seven, carbon atoms such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like.

Other etherified l8-hydroxyl groups have as the etherifying portions, represented, for example, by the radical R in the above-given formulae, other aliphatic radicals, such as, for example, lower alkenyl, particularly lower allylic alkenyl, containing preferably from three to five carbon atoms, e.g. allyl, Z-methyl-allyl, Z-butenyl, 3- methyl-2-butenyl, 2-pentenyl and the like, lower alkynyl, e.g. propargyl and the like, or cycloaliphatic radicals, such as cycloalkyl containing from three to eight, ring carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclo-octyl and the like, or cycloalkenyl, containing preferably from five to eight ring carbon atoms, e.g. 3-cyclopentenyl, Z-cyclohexenyl and the like.

Aliphatic radicals etherifying the 18-hydroxyl group, as represented by R in the above formulae, may contain substituents, such as, for example, cycloaliphatic radicals. Accordingly, substituted aliphatic radicals may be represented by cycloaliphatic-aliphatic radicals, for example, by cycloalkyl-lower alkyl, in which cycloalkyl contains from three to eight ring carbon atoms, and lower alkyl contains from one to four carbon atoms, e.g. cyclopropylmethyl, 2-cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, l-cyclopentylethyl, 2-cyclopentylethyl, 3-cyclopentylpropyl, cyclohexylmethyl, 2-cyclohexylethyl and the like, cycloalkyl-lower alkenyl, in which cycloalkyl has the above-given meaning, and lower alkenyl contains preferably from three to five carbon atoms, e.g. 3-cyclopropylallyl, 3-cyclopentyl-allyl and the like, cycloalkenyl-lower alkyl, in which cycloalkenyl contains from five to eight ring carbon atoms, and lower alkyl has from one to four carbon atoms, e.g. 2-(l-cyclopentenyl)-ethyl, 2-cycl0- hexenylmethyl, 3-cyclohexenylmethyl and the like.

Other substituted aliphatic radicals contain as substituents carbocyclic aryl groups and represent, for example, carbocyclic aryl-aliphatic radicals, such as monocyclic carbocyclic aryl-lower alkyl, particularly phenyllower alkyl, e.g. benzyl, diphenylmethyl, l-phenylethyl, 2- phenylethyl and the like, as well as carbocyclic-lower alkenyl, such as monocyclic carbocyclic aryl-lower alkenyl, particularly phenyl-lower alkenyl, e.g. 3-phenyl-allyl and the like, or analogous radicals, in which the carbocyclic aryl nucleus is substituted by one or more than one of the same or dilferent substituents, for example, by lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, lower alkenyloxy, e.g. allyloxy and the like, halogeno, e.g. fluoro, chloro, bromo and the like, lower alkoxy-carbonyloxy, e.g. methoxycarbonyloxy, ethoXy-carbonyloxy and the like, halogenolower alkyl, e. g. trifluoromethyl and the like, nitro, amino, such as N,N-di-lower alkyl-amino, e.g. N,N-dimethylamino and the like, or any other suitable substituent.

Other substituted aliphatic radicals, particularly lower alkyl groups, represented in the above formlae by the group R may be substituted by functional groups, particularly by hydroxyl or etherified hydroxyl. Aliphatic radicals containing hydroxyl groups are, for example, hydroXy-aliphatic radicals, such as hydroxy-lower alkyl, in which the hydroxyl group is separated from the l8-oxygen atom in the molecule by at least two carbon atoms, e.g. Z-hydroxyethyl, Z-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, S-hydroxypentyl and the like.

Etherified hydroxy-aliphatic radicals are primarily represented by lower alkoXy-lower alkyl, in which lower alkoxy contains from one to four carbon atoms, and stands, for example, for methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy and the like, and in which the lower alkoxy group is separated from the 18-oxygen atom in the molecule by at least two carbon atoms; lower alkoXy-lower alkyl groups may be represented by 2-lower alkoxyethyl, e.g.

Z-methoxyethyl,

Z-ethoxyethyl,

2-isopropyloxyethyl and the like,

2-lower alkoxy-propyl, e.g.

Z-methoxypropyl,

Z-ethoxypropyl,

Z-n-propyloxypropyl and the like,

3-lower alkoxypropyl, e.g. 3-methoxypropyl, 3-ethoxypropyl and the like, or any other analogous lower alkoxylower alkyl group.

Other etherified hydroxyl groups, which may substitute aliphatic, particularly lower alkyl, radicals are, for eX- ample, lower alkenyloxy, e.g. vinyloxy, allyloxy and the like, cycloalkyloxy, in which cycloalkyl has from three to eight ring carbon atoms, e.g. cyclopentyloxy, cyclohexyloxy and the like, cycloalkenyloxy, in which cycloalkenyl has from five to eight ring carbon atoms, e.g. 3- cyclohexenyloxy and the like, cycloalkyl-lower alkoxy, in which cycloalkyl has from three to eight ring carbon atoms, e.g. cyclopentylmethyloxy, 2-cyclohexylethyloxy and the like, lower alkoXy-lower alkoxy, e.g. Z-methoxyethoxy, Z-ethoxy-ethoxy, 3-methoXy-propyloxy and the like, w-lower alkoXy-alkoXy-poly-lower alkyleneoxy, e.g.

w-methoXy-diethyleneoxy,

w-ethoxy-diethyleneoxy,

w-methoXy-tetraethyleneoxy,

w-methoxy-nonaethyleneoxy, w-methoxy-dodecaethyleneoxy and the like, or any other suitably etherified hydroxyl group. Aliphatic, particularly lower alkyl, groups carrying such etherified hydroxyl groups are, for example, lower alkenyloXy-lower alkyl, in which the lower alkenyloxy group is separated from the 18-oxygen atom in the molecule by at least two carbon atoms, for example, 2-lower alkenyloxyethyl, e.g. 2-vinyloxyethyl, 2-allyloxyethyl and the like, 2-lower alkenyloxypropyl, e.g. 2-vinyloxypropyl and the like, 3-lower alkenyloxy-propyl, e.g. 3-vinyloxypropyl, 3-allyloxypropyl and the like, cycloalkyloXy-lower alkyl, in which cycloalkyloxy is separated from the 18-oxygen atom in the molecule by at least two carbon atoms, such as 2-cycloalkyloxy-ethyl, e.g. 2-cyclopentyloxy-ethyl and the like, Z-cycloalkyloxy-propyl, e.g. 2-cycloheXyloxy-propyl and the like, 3-cycloalkyl-propyl, e.g. 3-cyclopentyloXy-propyl and the like, cycloalkenyloxy-lower alkyl,

in which cycloalkenyloxy is separated from the l8-oxygen atom in the molecule by at least two carbon atoms, such as 2-cycloalkenyloxy-ethyl, e.g. 2-(2-cyclopentenyloxy)- ethyl and the like, 2-cycloalkenyloxy-propyl, e.g. 2-(3- cyclohexenyloxy)-propyl and the like, 3-cycloalkenyloxypropyl, e.g. 3-(3-cyclopentenyloxy)-propyl and the like, cycloalkyl-lower alkoxy-lower alkyl, in which cycloalkyllower alkoxy is separated from the l8-oxygen atom in the molecule by at least two carbon atoms, such as 2-(cycloalkyl-lower alkoXy)-ethyl, e.g. 2-cyclopentylmethyloxyethyl and the like, 2-(cycloalkyl-lower alkoXy)-propyl, e.g. 2-(2-cyclohexylethoxy)-propyl and the like, 3-cycloalkyl-lower alkoXy)-propyl, e.g. 3-cycloheXyl-methoxypropyl and the like,

lower alkoXy-lower alkoxy-lower alkyl, in which lower alkoxy-lower alkoXy is separated from the 18-oxygen atom in the molecule by at least two carbon atoms, such as 2- (lower alkoXy-lower alkoXy)-ethyl, e.g.

2- (-Z-methoxyethoxy) -ethyl,

2- (2-ethoXy-ethoxy) -ethyl, 2-(Z-isopropyloxyethoxy)-ethyl and the like,

2-(lower alkoXy-lower alkoxy)-propyl, e.g.

2- (Z-methoxyethoxy) -propyl, 2-(2-ethoXyethoXy)-propyl and the like,

3-lower alkoXy-lower alkoXy)-propyl, e.g.

3 (Z-methoxyethoxy) -propyl, 3-(2-ethoxyethoXy)-propyl and the like,

(w-lower alkoxy-poly-lower alkyleneoXy)-lower alkyl, in which w-lower alkoxy-poly-lower alkyleneoxy is separated from the 18-oxygen atom in the molecule by at least two carbon atoms, such as 2-(w-lower alkoxy-poly-lower alkyleneoxy)-ethyl, e.g. 2- (w-methoxydiethyleneoxy) -ethyl,

2- (w-ethoXy-tetraethyleneoxy) -ethy1, 2-(w-methoxy-nonaethyleneoxy)-ethyl and the like, Z-(w-lower alkoXy-poly-lower alkyleneoXy)-propyl, e.g. 2- (w-methoxy-triethyleneoxy) -propyl, 2-(w-ethoxy-tetraethyleneoxy)-propyl, 2-(w-methoxy-nonaethyleneoxy)-propyl and the like, 3-(w-lOW6I alkoXy-poly-lower alkyleneoXy)-propyl, e.g. 3 (w-methoXy-diethyleneoxy) -propyl, 3-(w-ethoxy-tetraethyleneoxy)-propyl, 3-(w-methoxy-nonaethyleneoxy)-propyl and the like,

or any other analogous aliphatic group carrying an etherified hydroxyl group.

Other substituted aliphatic, especially substituted lower alkyl, radicals contain as substituents esterified hydroxyl groups, such as lower alkoxy-carbonyloxy, e.g. methoxycarbonyloxy, ethoXy-carbonyloxy and the like, lower alkanoyloxy, e.g. acetoxy, propionyloxy andthe like, carbocyclic aryl-carbonyloxy, particularly monocyclic carbocyclic aryl-carbonyloxy, e.g. benzoyloxy, and benzoyloxy, in which the carbocyclic aryl portion is substituted by the same or different substituents attached to any of the positions available for substitution, such as, for example, by lower alkyl, e.g. methyl, ethyl, isopropyl and the like, lower alkoxy, e.g. methoxy, ethoxy, n-butyloxy and the like, lower alkenyloxy, e.g. allyloxy and the like, halogeno, e.g. fluoro, chloro, bromo and the like, lower alkoxy-carbonyloxy, e.g. methoxy-carbonyloxy, ethoxycarbonyloxy and the like, polyhalogeno-lower alkyl, e.g. trifiuoromethyl and the like, nitro, amino, such as N,N- di-lower alkyl-amino, e.g. N,N-dimethylamino and the like, or any other suitable substituent, carbocyclic aryllower aliphatic hydrocarbon-carbonyloxy, such as monocyclic carbocyclic aryl-lower alkanoyloxy or monocyclic carbocyclic aryl-lower alkenoyloxy, e.g. phenyl-acetoxy, 3-phenyl-propionyloxy, cinnamoyloxy and the like, and these radicals substituted in the carbocyclic nucleus by one or more than one of the same or of different substituents, such as those mentioned hereinbefore, or halogeno (representing a hydroxyl group esterified with a hydro-halic acid), e.g. fluoro and the like. Aliphatic, particularly lower alkyl, radicals substituted by esterified hydroxyl groups, in which the esterified hydroxyl group is separated from the 18-oxygen atom of the molecule by at least two carbon atoms, may be represented, for example, by lower alkoxy-carbonyloxy-lower alkyl, in which the esterified hydroxyl group is being separated from the 18- oxygen atom in the molecule by at least two carbon atoms, such as 2-lower alkoxy-carbonyloxy-ethyl, e.g. Z-methoxycarbonyloxy-ethyl and the like, 2-lower alkoxy-carbonyloxy-propyl, e.g. Z-ethoxy-carbonyloxy-propyl and the like, 3-lower alkoxy-carbonyloxy-propyl, e.g. 3-methoxy-carbonyloxy-propyl and the like, lower alkanoyloxy-lower alkyl, in which the esterified hydroxyl group is being separated from the 18-oxygen atom in the molecule by at least two carbon atoms, such as 2-lower alkanoyloxy-ethyl, e.g. Z-acetyloxy-ethyl, 2-propiony1-oxyethyl and the like, 2-lower alkanoyloxy-propyl, e.g. 2-acetyloxy-propyl and the like, 3-lower alkanoyloxy-propyl, e.g. 3-acetyloxy-propyl and the like, monocyclic carbocyclic aryl-carbonyloxy-lower alkyl, in which the esterified hydroxyl group is being separated from the 18-oxygen atom in the molecule by at least two carbon atoms, such as Z-monocyclic carbocyclic aryl-carbonyloxy-ethyl, e.g. Z-benzoyloxyethyl, 2-(3,4,S-trimethoxy-benzoyloxy)-ethyl, 2-(4-ethoxycarbonyl-syringoyloxy)-ethyl and the like, Z-monocyclic carbocyclic aryl-carbonyloxy-propyl, e.g. 2-benzoyloxy-propyl and the like,

3-monocyclic carbocyclic aryl-carbonyloxypropyl, e.g. 3-benzoyloxypropyl, 3-(3,4,5-trirnethoxy-benzoyloxy)-propyl and the like,

monocyclic carbocyclic aryl-lower alkanoyloxy-lower alkyl, in which the esterified hydroxyl group is separated from the 18-oxygen atom in the molecule by at least two carbon atoms, such as 2-monocyclic carbocyclic aryllower alkanoyloxy-ethyl, e.g.

2- 3- 3,4,5 -trimethoxy-phenyl) -propionyloxy] -ethyl and the like, 2-monocyclic carbocyclic aryl-lower alkanoyloxy-propyl,

e.g. Z-phenylacetyloxypropyl and the like, 3-monocyclic carbocyclic aryl-lower alkanoyloxy-propyl,

3-phenylacetyloxy-propyl and the like,

monocyclic carbocyclic aryl-lower alkenoyloxy-lower alkyl,

in which the esterified hydroxyl group is separated from the l8-oxygen atom in the molecule by at least two carbon atoms, such as Z-(monocyclic carbocyclic aryl-lower alkenyloxy)-ethyl,

2-cinnamoyloxyethyl and the like,

Z-monocyclic carbocyclic aryl-lower alkenoyloxy-propyl,

Z-cinnamoyloxy-propyl and the like,

3-(monocyclic carbocyclic aryl-lower alkenoyloxy)- propyl, e.g.

3-(3,4,S-trimethoxy-cinnamoyloxy)-propyl and the like,

halogeno-lower alkyl,

in which halogeno is separated from the 18-oxygen atom in the molecule by at least two carbon atoms such as, for example, Z-trifluoroethyl and the like.

Other aliphatic, particularly lower alkyl, radicals etherifying the 18-hydroxyl group and represented, for example, by R in the above formulae, may be substituted by acyl, particularly lower alkanoyl, e.g. acetyl, propionyl and the like, or carbo-lower alkoxy, e.g. carbomethoxy, carbethoxy and the like; such aliphatic radicals may be represented, for example, by lower alkanoyl-lower alkyl, e.g. acetonyl, butan-Z-onyl, butan-3-onyl and the like, carbo-lower alkoxy-lower alkyl, e.g. carbomethoxy-methyl, Z-carbethoxyethyl and the like.

Additional aliphatic, particularly lower alkyl, radicals etherifying the lS-hydroxyl group and represented, for

example, by R in the above formulae, may be substi tuted by mercapto or etherified mercapto, such as lower alkyl-mercapto, e.g. methylmercapto, ethylmercapto and the like, and represent mercapto-lower alkyl, in which the mercapto group is separated from the l8-oxygen atom in the molecule by at least two carbon atoms, e.g. 2-mercaptoethyl, 2-mercaptopropyl, B-mercaptopropyl and the like, or lower alkyl-mercapto-lower alkyl, in which lower alkyl-mercapto is separated from the lit-oxygen atom in the molecule by at least two carbon atoms, such as 2- lower alkylmercapto-ethyl, e.g. Z-methylmercaptoethyl, 2- ethylmercaptoethyl and the like, 2-lower alkyl-mercaptopropyl, e.g. Z-methylmercaptopropyl and the like, 3-lower alkyl-mercapto-propyl, e.g. S-ethylmercaptopropyl and the like.

Still other aliphatic, particularly lower alkyl, radicals etherifying the l8-hydroxyl group and represented, for example, by the group R in the above formulae, may be substituted by amino, particularly tertiary amino, such as N,N-di-lower alkylamino, e.g. N,N-dimethylamino, N-ethyl-N-methyl-amino, N,N-diethylamino, N,N-di-n-propylamino, N,N-di-isopropylamino, N,N-dibutylamino and the like, N,N-alkylene-imino,

in which alkylene contains from four to seven carbon atoms, e.g. l-pyrrolidino, l-piperidino, l-N,N-hexamethyleneirnino and the like, N,N-oxa-alkylene-imino, in which alkylene contains primarily four carbon atoms, e.g. 4- morpholino and the like, N,N-thia-alkylene-imino, in which alkylene has primarily four carbon atoms, e.g. 1- thiamorpholino and the like, N,N-aZa-alkylene-imino, in which alkylene contains from four to six ring carbon atoms, particularly 4-lower alkyl-l-piperazino, e.g. 4-methyl-l-piperazino, 4-ethyl-1-piperazino and the like. Aliphatic radicals substituted by a tertiary amino group are primarily tertiary amino-lower alkyl, such as N,N-di-lower alkyl-amino-lower alkyl, in which lower alkyl carrying the N,N-di-lower alkyl-amino group has from two to three carbon atoms and separates the tertiary amino group from the 18-oxygen atom in the molecule by at least two carbon atoms, for example,

2-N,N-di-lower alkylamino-ethyl, e.g. 2-N,N-dimethylaminoethyl, 2-N,N-diethyla.mino-ethyl and the like, 2-N,N-di-lower alkyl-amino-propyl, e.g. 2-N,N-dimethylaminopropyl, 2-N,N-diethylaminopropyl and the like, 3-N,N-di-lower alkyl-amino-propyl, e.g. 3-N,N-dimethylaminopropyl, 3,N,N-diethylaminopropyl and the like, l-N,N-alkylene-imino-lower alkyl,

in which lower alkyl has from two to three carbon atoms and separates the N,N-alkylene-imino group from the 18- oxygen atom in the molecule by at least two carbon atoms, and alkylene contains from four to seven carbon atoms, for example,

2-N,N-alkyleneimino-ethyl, e.g.

2-( 1-pyrrolidino -ethyl, 2-(l-piperidino) -ethyl and the like, 2-N,N-alkylene-imino-propyl, e.g. 2-(1-pyrrolidino)-propyl, and the like, 3- I,N-alkylene-imino-propyl, e.g. 3-(1-piperidino)-propyl and the like, 4-morpholino-lower alkyl,

in which lower alkyl has from two to three carbon atoms and separates the morpholino group from the l8-oxygen atom in the molecule by at least two carbon atoms, such as 2-(4-morpholino)-ethyl, 2-(4-morph0lino)-propy1, 3-(4- morpholino)-propyl, and the like, 4-lower alkyl-l-piperazino)-lower alkyl, in which lower alkyl, carrying the 4- lower alkyl-l-piperazino group, has from two to three carbon atoms and separates the 4-lower alkyl-l-piperazino group from the 18-oxygen atom in the molecule by at least two carbon atoms, for example, 2-(4-lower alkyl-lpiperazino)-ethyl, e.g. 2-(4-methyl-1-piperazino)-ethyl, 2- (4-ethy1-1-piperazino) -ethyl and the like, 2-(4-lower alkyl- 1-piperazino)-propyl, e.g. 2-(4-ethyl-1-piperazino)-propyl and the like, 3-(4-lower alkyl-l-piperazino)-propyl, e.g. 3-(4-methyl-1-piperazino) -propyl, 3-(4-ethyl g1 piperazino)-propyl and the like, as well as other analogous aliphatic radicals substituted by tertiary amino groups.

Aliphatic, particularly lower alkyl, radicals may also contain heterocyclic groups as substituents, which are attached to the aliphatic, e.g. lower alkyl, radical through one of their ring carbon atoms. Such groups are, for example, monocyclic heterocyclic aryl groups, especially monocyclic azacyclic aryl groups, such as pyridyl, e.g. 2- pyridyl, 4-pyridyl and the like, thienyl, e.g. Z-thienyl and the like or monocyclic cyclohetero-aliphatic groups, such as tetrahydrofuranyl, e.g. Z-tetrahydrofuranyl and the like. Aliphatic radicals substituted by a heterocyclic radical may be represented, for example, by pyridyl-lower alkyl, e.g. Z-pyridylmethyl, 2-(4-pyridyl)-ethyl, and the like, thienyl-lower alkyl, e.g. Z-thenyl and the like, tetrahydrofuranyl-lower alkyl, e.g. Z-tetrahydrofuranylmethyl and the like.

Substituents attached to any of the positions available for substitution in ring A, particularly those represented by the groups R R and R (each of which may also stand for hydrogen) in the previously given formulae, may be, for example, lower aliphatic hydrocarbon, especially lower alkyl, containing preferably from one to four carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, nbutyl, isobutyl, secondary butyl, tertiary butyl and the like, or functional groups, such as, for example, etherified hydroxyl, particularly lower alkoxy, containing preferably from one to four carbon atoms, e.g, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, secondary butyloxy, tertiary butylox and the like, as well as lower alkenloxy, e.g. allyloxy and the like, cycloalkyloxy, in which cycloalkyl contains from three to eight, preferably from five to six, ring carbon atoms, e.g. cyclopentyloxy, cyclohexyloxy and the like, cycloalkyl-lower alkoxy, in which cycloalkyl contains from three to eight, preferably from five to six, ring carbon atoms, e.g. cyclopentylmethoxy, Z-cyclopentylethoxy, cyclohexylmethoxy and the like, carbocyclic aryloxy, such as monocyclic carbocyclic aryloxy, e.g. phenyloxy and the like, carbocyclic aryl-lower alkoxy, such as monocyclic carbocyclic aryllower alkoxy, for example, phenyl-lower alkoxy, e.g. benzyloxy, diphenylmethoxy, 2-phenylethoxy and the like, esterified hydroxyl, particularly halogeno (representing hydroxyl esterified by a hydrohalic acid), particularly halogeno having an atomic weight of 19 to 80, e.g. fiuoro, chloro, bromo and the like, lower alkoxy-carbonyloxy, e.g. methoxycarbonyloxy, ethoxycarbonyloxy and the like, or lower alkanoyloxy, e.g. acetoxy, propionyloxy and the like, etherified mercapto, particularly lower alkylmercapto, containing preferably from one to four carbon atoms, e.g. methylmercapto, ethylmercapto and the like, nitro, amino, particularly N,N-disubstituted amino, such as N,N-di-lower alkyl-amino, e.g. N,N-dimethylamino, N- ethyl-N-methyl-amino, N,N-diethylamino and the like, polyhalogeno-lower alkyl, particularly trifluoromethyl and the like, or any other suitable functional group. A subst-ituent may also be attached to two adjacent positions of ring A and form a ring fused onto the A-ring; for example, two of the radicals R R and R in the formulae, when substituting two neighboring positions and taken together, may also form a fusedon cyclic substituent. Such substituents may be represented, for example, by lower alkylene-dioxy, e.g. methylenedioxy, l,l-ethylenedioxy and the like, or any other analogous grouping.

Substituents, which may be attached to other positions in the molecule, particularly to positions in ring C, which are available for substitution, are primarily aliphatic hydrocarbon, such as lower alkyl, containing preferably from one to four carbon atoms, particularly methyl, as well as ethyl, n-propyl, isopropyl and the like. The radical R in the previously given formulae, which stands primarily for hydrogen, may, therefore, also represent lower alkyl, particularly methyl, as well as ethyl and the like.

Salts of the compounds of this invention are primarily therapeutically and pharmacologically acceptable, nontoxic acid addition salts, particularly those with inorganic acids, such as mineral acids, e.g. hydrochloric, hydrogromic, sulfuric, phosphoric acids and the like, as well 'as with organic acids, e.g. acetic, maleic, citric, tartaric, methane sulfonic, ethane sulfonic, 1,2-ethane disulfonic, p-toluene sulfonic acid and the like.

Also included within the scope of the present invention are the N-oxides of the above-described com-pounds, as Well as the pharmacologically acceptable acid addition salts of these 'N-oxides, such as the addition salts with the above-mentioned inorganic, particularly mineral, and organic acids.

In view of the fact that several asymmetric carbon atoms are present in the compounds of this invention, the latter may be obtained in the form of a mixture of racemates, racemates or optically pure compounds.

The compounds of the present invention exhibit pharmacological properties and can be used accordingly. In contrast to the naturally occurring Rauwolfia diester alkaloids, the compounds of this invention react rapidly, the pharmacological action is of definite duration and the recovery from the eifects is complete; in other words, the compounds of this invention can be used in cases of emergency, and their actions are easily controllable. Furthermore, the non-toxic acid addition salts of these compounds are to a high degree water-soluble, and are, therefore, extremely useful in the preparation of pharmaceutical compositions, particularly of aqueous solutions for injection and aqueous oral preparations, e.g. elixirs and the like.

The compounds of this invention exhibit sedative and tranquilizing properties, as well as antihypertensive, antifibrillatory and/ or local anesthetic effects. The degree of and the ratio between each of these properties may vary considerably. Thus, some of the compounds of this invention show strong sedative and tranquilizing effects with negligible antihypertensive or antifibrillatory properties, whereas in others, these predominant sedative and tranquilizing activities are accompanied by beneficial antifibrillatory effects. Again others exhibit pronounced antihypertensive properties, while the sedative and tranquilizing components are much weaker. In addition to such diiferentiat-ions in the activity pattern, certain compounds of this invention exhibit local anesthetic properties.

Depending on the predominant pharmacological effects, the compounds of the present invention can, therefore, be used as sedative and tranquilizing agents to relieve states of hyperactivity, tension and agitation, as for example, associated with mental disturbances, anxiety and the like, as antihypertensive compounds to counteract hypertensive conditions, such as, for example, renal hypertension, toxemia and the like, in the treatment of cardiac irregularities, including extrasy-stoles, auricular fibrillation and the like, and/or as local anesthetics in connection with minor surgery or in the treatment of burns.

Compounds of this invention are particularly suitable in calming laboratory test animals, such as monkeys, cats, dogs and the like, prior to handling; some of the compounds can be used as local anesthetics during animal surgery performed, for example, in connection with the testing of pharmacologically active compounds influencing the functioning of certain organs, such as the adrenal glands, kidneys and the like.

Furthermore, compounds of this invention with sedative and tranquilizing effects can also be used in the veterinary field to quiet animals, particularly chickens, turkeys and the like, as well as other domestic animals to facilitate handling during vaccination, shipment and the like.

A preferred group of compounds is represented by the formula:

in which each of the letters In and n represents one of the whole numbers from one to seven, particularly from one to three, and R is lower alkoxy having from one to four carbon atoms, particularly methoxy, as well as ethoxy, n-propyloxy, isopropyloxy, n-butyloxy and the like, whereby R is preferably attached to the -position or the ll-position, or the non-toxic, pharmacologically acceptable acid addition salts thereof.

These compounds are represented by the lower alkyl 18-O-lower alkyl reserpates, in which lower alkyl has from one to seven, especially from one to three, carbon atoms, or the non-toxic, pharmacologically acceptable acid addition salts thereof, particularly by the methyl 18-O-lower alkyI-reserpates, in which lower alkyl has from one to three carbon atoms and is represented by methyl, ethyl, n-propyl or isopropyl, or the non-toxic, pharmacologically acceptable acid addition salts. Compounds of this type, particularly the above-mentioned methyl 18-O-lower alkyl-reserpates or the non-toxic, pharmacologically acceptable acid addition salts thereof, are characterized by predominant sedative and tranquilizing effects accompanied by negligible antihypertensive or antifibrillatory properties.

Another group of preferred compounds may be represented by the formula:

in which each of the letters In and n represents one of the whole numbers from one to seven, particularly from one to three, and R represents lower alkoxy having from one to four carbon atoms, particularly methoxy, as well as ethoxy, n-propyloxy, isopropyloxy, nbutyloxy and the like, whereby R is preferably attached to the 10-position or the ll-position, or the non-toxic pharmacologically acceptable acid addition salts thereof.

These compounds are represented by the lower alkyl l8-epi-O-lower alkyl-reserpates, in which lower alkyl has from one to seven, especially from one to three carbon atoms, particularly by the methyl 18-epi-O-1ower alkylreserpates, in which lower alkyl has from one to three carbon atoms and is represented by methyl, ethyl, n-propyl or isopropyl, or the non-toxic pharmacologically acceptable acid addition salts thereof. Compounds of this type, particularly the above-mentioned methyl l8-epi-O- lower alkyl-reserpates or the non-toxic, pharmacologically acceptable acid addition salts thereof, are characterized by strong sedative and tranquilizing properties which can be accompanied by anti-fibrillatory and local anesthetic effects, but show only negligible antihypertensive activi- I165.

L Q- (c n yon l-Z in which the letter n represents one of the whole numbers from one to seven, particularly from one to three, and the letter p stands for one of the whole numbers from two to seven, particularly from two to five, and in which the radical of the formula (C H separates the two oxygen atoms attached to such radical by at least two carbon atoms, and R is lower alkoxy having from one to four carbon atoms, particularly methoxy, as Well as ethoxy, n-propyloxy, isopropyloxy, n-butyloxy and the like, whereby R is preferably attached to the l0-position or the ll-position, or the non-toxic, pharmacologically acceptable acid addition salts thereof.

These compounds are primarily represented by the lower alkyl 18-epi-O-(hydroxy-lower alky1)-reserpates, in which lower alkyl of the ester group has from one to seven, especially from one to three carbon atoms, and lower alkyl of the hydroxy-lower alkyl group has from two to seven, particularly from two to five carbon atoms separating the hydroxyl group from the 18-oxygen atom by at least two carbon atoms, or the non-toxic, pharmacologically acceptable acid addition salts thereof, particularly by the methyl IS-epi-O-(hydroxy-lower alkyl)-reserpates, in which lower alkyl has from two to five carbon atoms separting the hydroxyl group from the 18-oxygen atom by at least two carbon atoms, or the non-toxic pharmacologically acceptable acid addition salts thereof. Compounds of this type, particularly the above-mentioned methyl 18-epi-O-(hydroxy-lower alkyl)-reserpates or the non-toxic, pharmacologically acceptable acid addition salts thereof, show strong sedative and tranquilizing properties, accompanied by negligible antihypertensive effects.

Another group of preferred compounds having outstanding sedative and tranquilizing properties is represented by the formula:

H OCH in which the letter In stands for one of the whole numbers from one to seven, particularly from one to three, the letter w stands for one of the whole numbers from one to four, and the letter y stands for one of the whole numbers from two to three, and in which the radical of the formula (C H )separates the two oxygen atoms attached to such radical by at least two carbon atoms, and R represents lower alkoxy having from one to four carbon atoms, particularly methoxy, as well as ethoxy, n-propyloxy, isopropyloxy, n-butyloxy and the like, whereby R is preferably attached to the 10-position or the ll-position, or the non-toxic, pharmacologically acceptable acid addition salts thereof.

Compounds of the above type are primarily the lower alkoxy-lower alkyl 18-epi-O-lower alkyl-reserpates, in which lower alkyl substituting the 18-oxygen atom has from one to seven, especially from one to three carbon atoms, and lower alkyl of the lower alkoxy-lower alkyl group has from two to three carbon atoms, which separate the lower alkoxy group having from one to four carbon atoms, by at least two carbon atoms from the l6B-carboxyl group, or the non-toxic, pharmacologically acceptable acid addition salts thereof. Compounds of this type, particularly the above-mentioned lower alkoxy-lower alkyl l8-epi-O-lower alkyl-reserpates or the non-toxic, pharmacologically acceptable acid addition salts thereof, are characterized by strong sedative and tranquilizing effects and show only negligible antihypertensive properties.

A further group of preferred compounds is represented by those having the formula:

in which each of the letters w and x stands for one of the whole numbers from one to four, and each of the letters y and z stands for one of the whole numbers from two to three, and each of the radicals of the formulae (C H and (C H separates the two oxygen atoms attached to such radicals by at least two carbon atoms, and R is lower alkoxy having from one to four carbon atoms, particularly methoxy, as well as ethoxy, n-propyloxy, isopropyloxy, n-butyloxy and the like, whereby R4 is preferably attached to the l-position or the ll-position, or the non-toxic, pharmacologically acceptable acid addition salts thereof.

Compounds of the above type are primarily the lower alkoxy-lower alkyl 18-epi-O-(lower alkoxy-lower alkyl)- reserpates, in whihch lower alkyl has from two to three carbon atoms, which separate the lower alkoxy group, having from one to four carbon atoms, by at least two carbon atoms from the 16,8-carboxyl group and the 18- oxygen atom, respectively, or the non-toxic, pharmacologically acceptable acid addition salts thereof. Compounds of this type, particularly the above-mentioned lower alkoxy-lower alkyl 18-epi-O-lower alkoxy-lower alkyl-reserpates or pharmacologically acceptable acid addition salts thereof, have antihypertensive properties accompanied by less pronounced and negligible sedative and tranquilizing eifects.

The compounds of this invention may be used in the form of pharmaceutical preparations, which contain the new compounds or derivatives thereof, such as non-toxic, pharmacologically acceptable acid addition salts, N-oxides or pharmacologically acceptable acid addition salts of N-oxides thereof, in admixture with a pharmaceutical organic or inorganic, solid or liquid carrier suitable for enteral or parenteral administration. For making up the preparations there can be employed inert substances, which are compatible with the new compounds, such as water, gelatine, lactose, starches, stearic acid, magnesium stearate, stearyl alcohol, talc, vegetable oils, benzyl alcohols, gums, waxes, propylene glycol, polyalkylene glycols or any other known inert carrier used in pharmaceutical preparations. These may be in solid form, for example, as tablets, capsules, dragees and the like, or in liquid form, for example, as solutions, suspensions, emulsions and the like. If desired, they may contain additional substances, such as preserving, stabilizing, wetting, emulsifying agents and the like, salts for varying the osmotic pressure, buffers or any other auxiliary substances. They may also contain in combination, other therapeutically useful substances.

Compounds of this invention can be formed by etherifying in an 18-hydroxy-3-epiallo-yohirnbane l6fl-carboxylic acid ester, a salt, an N-oxide or a salt of an N-oxide thereof, the free hydroxyl group attached to the 18-position by treatment with a diazo-compound in the presence i l of a strong inorganic Lewis acid, and, if desired, converting a resulting salt into the free base, and/or, if desired, converting a resulting compound into a salt, an N-oxide or a salt of an N-oxide thereof, and/or, if desired, converting a resulting mixture of isomers into the single isomers.

A salt of the starting material or of an N-oxide thereof, is an addition salt with an acid, primarily a salt with an inorganic, such as a mineral, acid, e.g. hydrochloric, hydrobromic, sulfuric, phosphoric acid and the like. An acid addition salt may also be a salt with the strong inorganic Lewis acid catalyzing the etherification reaction, e.g. fluoboric acid and the like; such salt may be formed during the reaction.

The starting material is reacted with the diazo compound, particularly a lower diazo-alkane, e.g. diazomethane, diazoethane, n-diazopropane, n-diazobutane, diazoisobutane, n-diazopentane and the like, or any other suitable diazo reagent, in the presence of a strong inorganic Lewis acid. Fluoboric acid, which may be employed in the form of a concentrated aqueous solution (for example, as an about 12 N to an about 16 N aqueous solution) represents the preferred reagent. Other Lewis acid acid reagents may be, for example, perchloric acid (preferably in anhydrous form) and the like. Due to the saltforming properties of free starting material, the Lewis acid, catalyzing the etherification of the iii-hydroxyl group, is used in excess of one mol, whenever the free base is present; an about one to an about two hundred, preferably an about ten to an about fifty, percent excess appears to be sufficient to promote the etherification reaction.

The reaction is carried out in the presence of an organic solvent, which is inert towards the starting material, the diazo reagent and the Lewis acid. Appropriate diluents are,- for example, halogenated lower aliphatic hydrocarbons, e.g. methylene chloride, chloroform, ethylene chloride, trichloroethane, tetrachloroethane and the like, ethers, e.g. dlethylether, tetrahydrofuran and the like, lower alkyl lower alkanoates, e.g. methyl acetate, ethyl acetate and the like, acetonitrile or any other useful solvent, as well as mixtures of solvents, such as those mentioned hereinabove. A solution of the diazo reagent in an inert solvent, such as an ether, e.g. diethyl ether and the like, or a halogenated hydrocarbon, e.g. methylene chloride and the like, or a mixture of solvents, may be added to the mixture of the starting material and the Lewis acid, preferably kept in solution. The diazo compound may also be distilled out of a solution into the solution of the mixture of the starting material and the Lewis acid. Furthermore, the latter mixture may also be given to a solution of the diazo reagent.

, The reaction may be carried out at room temperature; however, cooling of the reaction mixture to below room temperature, for example, to from about 10 to about -20, especially to from about 0 to about -15", may be advantageous. If necessary, the reaction may be carried out in the atmosphere of an inert gas, e.g. nitrogen and the like.

An excess of the diazo reagent present at the end of the reaction may be destroyed, for example, by adding an acid, preferably an easily esterifiable organic carboxylic acid, e.g. acetic, benzoic acid and the like.

The desired product may be isolated and separated from any by-products according to standard procedures, e.g. extraction, adsorption and elution, crystallization, etc. and purified, for example, by recrystallization, if necessary after treatment of a solution thereof with an adsorbent, e.g. aluminum oxide, charcoal, diatomaceous earth and the like.

Starting materials used in the above procedure are known. Others, such as the 18a-hydroxy-3-epi-allo-yohimbane 16fi-carboxylic acid esters, may be prepared, for example, by reacting an 18 8-organic sulfonyl0xy-3-epiallo-yohimbane 16fi-carboylic acid ester, in which the organic radical represents primarily monocyclic carbocyclic aryl, such as phenyl, or substituted phenyl, a salt, an N-oxide or a salt of an N-oxide thereof, with water to form the desired l8a-hydroxy-3-epi-allo-yohimbane 16B- carboxylic acid ester, and, if desired, converting a resulting compound into a salt, an N-oxide or a salt of an N-oxide thereof.

Substituted phenyl groups may contain one or more than one substituent in any of the positions available for substitution. Preferred substituents are nitro or halogeno, such as bromo, as well as chloro, iodo and the like; other suitable groups, such as methyl and the like, may also be attached to the phenyl radical. The organic portion in the organic sulfonyloxy group may, therefore, be represented by nitro-phenyl, e.g. 3-nitro-phenyl, 4-nitro-phenyl and the like, halogeno-phenyl, e.g. 4-bromo-phenyl and the like, as well as by phenyl and the like. It may also stand for another organic radical, such as an aliphatic radical, for example, lower alkyl, e.g. methyl, ethyl and the like.

Hydrolysis of the organic sulfonyloxy group in the 18,8- organic sulfonyloxy-3-epi-allo-yohimbane 16,8-carboxylic acid ester, may be carried out by treatment with water, preferably in the presence of an amine, especially a tertiary amine, such as, for example, an N,N,N-tri-lower alkyl-amine, e.g. N,N,N-trimethylamine, N-ethyl-N-N-dimethylamine, N,N,N-triethylamine and the like, or any other suitable amine. Hydrolysis is achieved by heating the mixture to an elevated temperature, preferably in a closed vessel and/or in the atmosphere of an inert gas, e.g. nitrogen. The hydrolysis reaction proceeds with in version, i.e. the ISB-organic sulfonyloxy-3-epi-allo-yohimbane 16,8-carboxylic acid ester yields upon hydrolysis according to the above procedure the 18a-hydroxy-3-epiallo-yohimbane 16,8-carboxylic acid ester.

The above l85-organic sulfonyloxy-3-epi-allo-yohimbane IGB-carboxylic acid esters used as the intermediates may be prepared according to known methods, for example, by esterification of an l8fi-hydroxy-3-epi-alloyohimbane 16/9-carboxylic acid ester with an organic sulfonyl halide, particularly a monocyclic aryl sulfonyl halide, such as benzene sulfonyl chloride, or a substituted benzene sulfonyl chloride, e.g. 3-nitro-benzene sulfonyl chloride, 4-nitro-benzene sulfonyl chloride, 4-bromo-ben zene sulfonyl chloride and the like, in the presence of a base, particularly an organic tertiary base, e.g. pyridine, collidine and the like. In the esterification step, the base, such as, for example, pyridine and the like, may also serve as the diluent; other suitable, inert solvents may be added, if necessary. The reaction is carried out under cooling or at room temperature, preferably under the exclusion of moisture.

The IS-etherified hydroxy-3-epi-allo-yohimbane 16 8- carboxylic acid esters, salts, N-oxides or salts of N-oxides thereof may also be prepared, for example, by subjecting an l8-organic sulfonyloxy-3-epi-allo-yohimbane l6B-carboxylic acid ester, a salt, an N-oxide or a salt of an N- oxide thereof, to solvolysis wtih an alcohol, and, if desired, carrying out the optional steps.

The organic portion of the organic sulfonyloxy group has the previously given meaning, and is primarily a monocyclic carbocyclic aryl group, which may be represented by phenyl, or, more particularly, by substituted phenyl. The latter is preferably a phenyl radical substituted in the 2-position, 3-position and/ or the 4-position by an electron-withdrawing substituent, particularly nitro or halogeno, such as bromo, as well as fluoro, chloro or iodo, as well as carbo-lower alkoxy, e.g. carbomethoxy, carbethoxy and the like, carbamyl, cyano or any other suitable groups. Lower alkyl, especially methyl and the like, may also be a suitable substituent. The organic portion may, therefore, be represented by phenyl, or primarily by halogeno-phenyl, e.g. 4-bromo-phenyl and the like, or nitro-phenyl, e.g. 3-nitrophenyl, 4-nitro-phenyl and the like, as well as cyano-phenyl, e.g. 4-cyano-phenyl 5 and the like, or di-substituted or tri-substituted phenyl radicals containing such groups. The organic radical may also stand for other organic radicals, such as an aliphatic radical, for example, lower alkyl, e.g. methyl, ethyl and the like.

solvolysis with the alcohol may be carried out in the absence, but more preferably in the presence of an alcoholysis reagent. Such reagent is represented by an amine, such as a tertiary amine, especially an aliphatic tertiary amine, such as an N,N,N-tri-lower alkyl-amine, e.g. N,N,N trimethylamine, N ethyl N,N dimethylamine, bLN-diethyl-N-methylamine, N,N,N-triethylamine and the like, an N,N,N,N',-tetra-lower alkyl-lower alkylene-diamine, e.g. N,N,N',N-tetramethyl-1,5-pentylene-diamine, N,N,N,N'-tetramethyl-l,6-hexylenediamine, N,N,N',N- tetramethyl-l,7-heptylcne-diamine and the like, a l-lower alkyl-N,N-alkylene-imine, in which alkylene contains from four to six carbon atoms, e.g. l-methyl-pyrrolidine, l-methyl-piperidine, l-ethyl-piperidine, l-methyl-N,N-hexamethylene-imine and the like, 4-lower alkyl-morpholine, e.g. 4-methyl-morpholine, 4-ethyl-morpholine and the like, 1,4-di-lower alkyl-piperazine, e.g. 1,4-dimethyl-piperazine and the like, or any other suitable aliphatic tertiary amine, as well as a heterocyclic base containing a tertiary nitrogen atom, e.g. pyridine, colloidine and the like, or any other suitable base.

The solvolysis may be carried out using the alcohol, for example, a lower alkanol and the like, as the diluent; any other inert solvent such as, for example, p-dioxane and the like, may be added to ensure complete solution. The reaction is preferably completed at an elevated temperature, if necessary, in a closed vessel under an increased pressure, and/or in the atmosphere of an inert gas, such as nitrogen.

The solvolysis occurs with inversion; thus, an 18B- organic sulfonyloxy-3-epi-allo-yohimbane 16/9-carboxylic acid ester, upon treatment with an alcohol, yields an 1811.- etherified hydroxy-3-epi-allo-yohimbane 16,8-carboxylic acid ester, and vice versa.

The 18-organic sulfonyloxy-3-epi-allo-yohimbane 16B carboxylic acid esters, salts, N-oxides or salts of N-oxides may be prepared as previously shown, for example, by esterification of an l8-hydroxy-3-epi-allo-yohimbane 16,3- carboxylic acid ester.

New and particularly suitable as intermediates are the 18 8 (halogeno phenyl) sulfonyloxy 3 epi -alloyohimbane 16-carboxylic acid esters and the ISIS-(111K0- phenyl) sulfonyloxy 3 epi allo yohimbane 1613- carboxylic acid esters, particularly the compounds of the formula:

in which R R R R R and K, have the previously given meaning, and Ar represents halogeno-phenyl or nitro-phenyl, salts, N-oxides and salts of N-oxides thereof, which compounds are intended to be included within the scope of this application. These compounds are preferred intermediates used in the conversion of compounds with the ISfl-configuration into those having the 18a-configuration, i.e. the conversion of compounds derived from natural sources or from known totally synthetic procedures into compounds of the IS-epi-series, either according to the above-described solvolysis or the previously shown hydrolysis to the desired lSa-hydroxy-B-epi-allo-yohimbane 16B-carboxylic acid esters used as intermediates in the etherification procedure.

the ISu-series are those having the formulae:

in which the letter n represents one of the whole numbers from one to seven, especially from one to three, the letter w represents one of the whole numbers from one to four, and the letter y stands for one of the whole numbers from two to three, and in which the radical of the formula -(C H separates the two oxygen atoms attached to such radical by at least two carbon atoms, and R represents lower alkoxy, having from one to four carbon atoms, particularly methoxy, as well as ethoxy, n-propyloxy, isopropyloxy, n-butyloxy and the like, whereby R is preferably attached to the -position or the ll-position, and in which the nitro group is preferably located in the 3-position or the 4-position of the phenyl portion of the 185-(nitro-phenyl-sulfonyloxy)-substituent, or acid addition salts of such compouds. Preferred members of this group of compounds are the lower alkyl 18-O-(nitro-phenyl-sulfonyl)-reserpates, especially the methyl 18-0-(nitrophenyl-sulfonyl)-reserpates, as well as the 2-lower alkoxyethyl 18-0- (nitro-phenyl-sulfonyl) -reserpates, particularly the 2-methoxy-ethyl 18-O-(B-nitro-phenyl-sulfonyl)-reserpate or Z-methoxyethyl 18-O-(4-nitro-phenyl-sulfonyl)- reserpate, or acid addition salts of such compounds.

Another group of important intermediates is represented by the following formulae:

in which the letter n represents a whole number from one to seven, especially from one to three, the letter w represents one of the whole numbers from one to four, and the letter y stands for one of the whole numbers from two to three, and in which the radical of the formula separates the two oxygen atoms attached to such radical by at least two carbon atoms, and R represents lower alkoxy, having from one to four carbon atoms, particularly methoxy, as well as ethoxy, n-propyloxy, isopropyloxy, n-butyloxy and the like, whereby R is preferably attached to the l0-positi0n or the ll-position, and in which bromo is preferably located in the 4-position of the phenyl portion of the l8,8-O-halogeno-phenyl-sulfonyloxy group, or acid addition salts of such compounds. Preferred members of this group are the lower alkyl IS-O-(bromophenyl-sulfonyl)-reserpates, particularly methyl 18-0-(4- bromophenyl-sulfonyl)-reserpate, as well as 2-l0wer alkoxy-ethyl 18-0- (bromo-phenyl-sulphonyl) -reserpates, particularly the 2-methoxy-ethyl l8-0-(4-bromo-phenylsulphonyl)-reserpate, or acid addition salts of such compounds. Apart from being valuable intermediates, the above-mentioned 18 8-organic sulfonyloxy-3-epi-all0-yohimbane 16,8-carboxylic acid esters, salts, N-oxides or salts of N-oxides thereof show sedative and tranquilizing properties and can be used accordingly.

The compounds of the present invention may also be prepared by removing in a A -l8-etherified hydroxy-alloyohimbene -carboxylic acid ester or a salt of such compound, the double bond extending from the -position by reduction and, if desired, carrying out the optional steps.

The double bond in the starting material is in the 3(14)- position or in the 3(4)-position; in a free base or in the latter in solution in a non-polar solvent, the double bond is in the 3(14)-position, whereas in a salt, in the latter in solution or in the free base in solution in a polar solvent, the double bond is in the 3(4)-position.

In the above-described starting material, the anion of a salt stands primarily for the anion of a strong inorganic acid, particularly a mineral acid, such as a hydrohalic acid, e. g. hydrochloric, hydrobromic acid and the like, or phosphoric acid, a halogenophosphoric acid, e.g. chlorophosphoric acid and the like, or perchloric acid or any other suitable acid; it may also represent the anion of an organic acid. A salt with an organic acid may be present whenever a solution of the starting material in an organic acid, e.g. acetic acid and the like, is used in the abovedescribed removal procedure. The conversion of one form into the other may be carried out according to known methods. Thus, a free compound yields the salt upon reaction with an acid, or by treatment of the salt with an alkaline reagent, particularly ammonia, preferably in an anhydrous medium, or any other suitable base, the free compound may be obtained. In the previously described method, acidic conditions prevail; therefore, Whenever the starting material is given to the reaction mixture in the form of the free compound, the salt is formed in situ.

The removal of the double bond is carried out according to known reduction methods yielding the desired 18- etherified hydroxy-3-epi-allo-yohimbane 16fi-carboxylic acid ester compounds, particularly by treating a solution of the starting material in an acid, such as, for example, acetic acid (preferably in the form of aqueous acetic acid), perchloric acid and the like, with a metal. Together with the acid, the metal furnishes the reducing reagent capable of reducing the double bond; zinc, in the presence of an acid, e.g. acetic, perchloric acid and the like, yields a very useful reducing reagent. Zinc in the presence of perchloric acid, which may be used in an aqueous mixture or in admixture with another acid, e.g. acetic acid and the like, represents the preferred reagent; this reagent is particularly suitable, because the rate of reduction is fast and any contact of the starting material, as well as the reduction product with the acidic medium can be kept to a minimum. Organic diluents, such as ethers, e.g. tetrahydrofuran, p-dioxan and the like, lower l9 alkanones, e.g. acetone and the like, or any other suitable solvent may be present as additional diluents, if desired, together with water. The reaction may be carried out at room temperature, or, if necessary, under cooling or at any elevated temperature.

The product of the reduction procedure may be isolated, for example, by neutralizing the acidic reaction mixture with an alkaline reagent, e.g. ammonia and the like, if desired, after removing the solvent or part of it, and extracting the organic material with a suitable solvent, e.g. methylene chloride and the like, or by any other appropriate isolation method.

The above-mentioned starting materials may be prepared, for example, by reacting an IS-etherified hydroxy- 3-oxo-2,3-seco-allo-yohin1bane l6B-carboxylic acid with a ring-closing reagent, and, if desired, converting a resulting salt into the free compound, and/or, if desired, converting a free compound into a salt thereof.

Ring closure of the above-described 2,3-seco-allo-yohimbane compoundsrnay be carried out according to konwn methods, for example, by treatment with an acidic ring closing reagent, for example, a phosphoric acid, e.g. polyphosphoric acid and the like, a phosphorus halide, e.g. phosphorus trichloride, phosphorus pentachloride, or advantageously a phosphorus oxyhalide, e.g. phosphorus oxychloride and the like.

The 2,3-seco-allo-yohimbane compounds used as the intermediates in the preparation of the A -allo-yohimbene starting materials may be prepared according to different procedures. For example, in an l8-hydroxy-3-oxo-2,3- seco-allo-yohimbane 16fl-carboxylic acid ester compound, the free hydroxyl group may be etherified. Etherification may be carried out according to the previously mentioned etherification procedure, for example, by treatment with a diazo compound in the presence of fluoboric acid or any other suitable Lewis acid. Etherification may also be achieved according to other known procedures, for example, by treatment with other reagents suitable for the etherification of a secondary hydroxyl group. Such reagents are, for example, reactive esters formed by hydroxylated compound with strong acids, such as inorganic acids, e.g. hydrochloric, hydrobromic, hydriodic, sulfuric acid and the like, or with organic acids, particularly strong organic sulfonic acids, e.g. p-toluene sulfonic acid and the like, which reagents are preferably used in the presence of reagents facilitating the etherification procedure. The above etherification procedure is particularly suitable for the preparation of 3-oxo-2,3-seco-allo-yohimbane compounds which can be prepared directly from products obtained according to known totally synthetic methods.

The intermediate 3-oxo-2,3-seco-allo-yohimbane compounds may also be prepared by esterifying in an l8-hydroxy-3-oxo-2,3-seco-allo-yohimbane l6fi-carboxylic acid ester the free hydroxyl group by treatment with an organic sulfonic acid halide, particularly a monocyclic carbocylic aryl sulfonyl halide, as Well as an aliphatic sulfonic acid halide, and subjecting a resulting l8-organic sulfonyloxy- 3-ox0-2,3-seco-allo-yohimbane l6 8-carboxylic acid ester to solvolysis with an alcohol. Esterification with an organic sulfonic acid halide, for example, with a (halogenophenyl)-sulfonyl chloride, a (nitro-phenyl)-sulfonyl chloride and the like, is carried out as previously shown, for example, in the presence of an organic base, e.g. pyridine and the like. Alcoholysis of the l8-organic sulfonyloxy group may be achieved according to the procedure described hereinbefore, preferably in the presence of a base, such as an organic amine, e.g. N,N,Ndiethylamine, pyridine and the like. As has been shown hereinbefore, solvolysis of an 18-organic sulfonyloxy group occurs with inversion at the 18-carbon atom. This procedure is particularly suitable for the preparation of 3-0xo-2,3-secoyohimbane compounds with an l8-etherified hydroxyl group having the tit-configuration, i.e. compounds, which can be prepared from products obtained according to known totally synthetic methods.

The 18a-hydroxy-3-oxo-2,3-seco-allo-yohimbane 16/3- carboxylic acid esters, which compounds can be used either in the above etherification procedure to form the IBa-etherified hydroxy-3-oxo-2,3 seco allo yohimbane IGB-carboxylic acid esters or in the esterification to the ISa-Organic sulfonyloxy-3-oxo-2,3-seco allo yohimbane 16/3-carboxylic acid esters, may be obtained, for example, by hydrolysis of 18B-organic sulfonyloxy-3-oxo-2,3-secoallo-yohimbane lofi-carboxylic acid esters with water, preferably in the presence of a base, such as an organic amine. Such hydrolysis procedure is carried out according to methods previously described in detail.

The l8-etherified hydroxy-3-oxo-2,3-seco-allo-yohimbane 16fl-carboxylic acid esters, used as the intermediates for the preparation of the starting materials may also be prepared, for example, by ring closure of an IBetherified hydroxy-3-lower alkoxy-3-oxo-2,3;3,4-bis-seco-allo-yohimbane 16,8-carboxylic acid ester or a salt thereof. Ring closure may be achieved according to known methods, for example, by treatment of the ester with a carboxylic acid anhydride, e.g acetic acid anhydride and the like, or any other analgous ring-closing reagent.

The 2,3 ;3,4-bis-seco-allo-yohimbane compounds used in the above procedure may be prepared, for example, by etherifying in a 3B-hydroxy-7-oxo-1a,2/3,3u,4,7,8,9a,10aoctahydro-naphthalene IB-carboxylic acid ester the free hydroxyl group according to previously given methods used for the etherification of secondary hydroxyl groups, to form a 3;8-etherified hYdI'OXY-7-0XO-1a,2fi,3a,4,7,8,9u, 1 0a-octahydro-naphthalene lfi-carboxylic acid esters. Or, a 3,8 hydroxy-7 oxo lcc,2fi,3a,4,7,8,9cc,IOa-OdahydrO- naphthalene lfl-carboxylic acid ester may be reacted with an organic sulfonic acid halide, preferably a monocyclic carbocyclic aryl-sulfonyl chloride, in the presence of an organic base, and a resulting Pip-organic sulfonyloxy-7- oxo-lu,2fl,3a,4,7,8,9a,lOu-octahydromaphthalene lfl-carboxylic acid ester may be subjected to solvolysis with an alcohol, preferably in the presence of an organic tertiary base to form a 3a-etherified hydroxy-7-oxo-1a,2/3,3/3,4,7,8, 9a,lOa-OctahydrO-naphthaIene lfi-carboxylic acid ester. The above-mentioned 3-etherified hydroxy-7-oxo-1a,2,8,3, 4,7,8,9a,lOa-octahydro-naphthalene lB-carboxylic acid esters are then oxidized, for example, with osmium tetroxide in an aqueous solution, followed by treatment with sodium chlorate, to form 5a,6a-dihydroxy-3-etherified hydroxy 7 oxo 1a,2;3,3,4,5/8,7,8,9a,IOa-decahydro-na hthalene lp-carboxylic acid esters, which diols are then oxidatively split, for example, by treatment with periodic acid hydrate in an aqueous medium, to form Sir-aldehyde- Z-etherified hydroxy-GB-carboxymethyl-111,25,3,4,5a,6ahexahydro-benzene lfl-carboxylic acid esters. The free carboxyl group of the carboxymethyl portion is then esterified, for example, with a lower diazoalkanc, e.g. diazomethane, diazoethane and the like, to form the desired 5,9-aldehydo-3-etherified hydroxy-6fi-carbo-lower alkoxymethyl-111,2,6,3,4,5a,6a-hexahydro-benzene lfi-carboxylic acid esters, which compounds are then reacted with a tryptamine, preferably in solution with an inert solvent, e.g. benzene and the like, to yield A -l8-etherified hydroxy-3-lower a1koxy-3-oxo-2,3;3,4-bis-seco-allo-yohimbene l6fl-carboxylic acid esters. Upon treatment with a reducing reagent, for example, with a borohydride, e.g. sodium borohydride and the like, in an inert solvent, such as a lower alkanol, e.g. methanol, ethanol and the like, and, if necessary, in the presence of an activator, e.g. aluminum chloride and the like, the Schiff-base type double bond is reduced, and the desired IS-etherified hydroxy-B-lower a1k0xy3-oxo-2,3,3,4-bis-seco-allo-yohimbane 16B-carboxylic acid esters are formed, in which the esterified carboxyl groups may be partially or totally hydrolized. Hydrolized carboxyl groups may subsequently be re-esteritied, for example, by treatment with a lower aliphatic diazo-hydrocarbon, such as a lower diazoalkane, particularly diazomet-hane, as well as diazoethane and the like, or any other suitable diazo-reagent.

The Sfl-aldhehydo-El-etherifie=d hydroxy-6fl-carbo-lower alkoxy-methyl-la,2fi,3,4,5a,6u-hexahydro-benzene lli-carboxylic acid ester may also be prepared, for example, by directly etherifying, or esterifying with an organic sulfonic acid halide and subsequently alcoholizing with an alcohol, the free hydroxyl group in a 3-hydroXy-7-oxo-10,2fl,3,4,7, 8,90,1Oa-octahydro-naphthalene lfi-carboxylic acid ester, which reactions are carried out according to the previously described methods. A resulting 3-etherified hydroxy 7 x0 1ot,2,8,3,4,7,8,9a,100t octahydro naphthalene lfl-carboxylic acid ester is then subjected to the treatment of ozone in the presence of an inert organic solvent, for example, in glacial acetic acid, ethyl acetate and the like, and at temperatures between about 0 and about -60 to effect ozonation, the excess ozone is removed from the reaction mixture, for example, by bubbling an inert gas, e.g. nitrogen and the like, through the reaction solution, and the resulting ozonide is decomposed by adding water at room temperature to form the desired 55- aldehydO-Bretherified hydroxy-6fi-carboxymethyl-104,2 83, 4,5a,6a hexahydrobenzene lfi-carboxylic acid ester, in which the free carboxyl group is then esterified as previously shown to yield the desired intermediate, which is condensed with the tryptamine compound.

The etherification of a free hydroxyl group, with or without simultaneous inversion, may also be carried out at any other suitable step of the aboveshown procedures leading to the desired intermediates for the preparation of the starting materials.

The A -18-etherified hydroxy-allo-yohimbene 16,3-carboxylic acid esters or salts thereof, which compounds are used as starting materials for the preparation of the 18- etherified hydroxy-3-epi-allo-yohimbane l6fl-carbo-xylic acid esters according to the previously described procedure, may also be prepared, for example, by ring closure of an 18-organic sulfonyloxy-3-oxo-2,3-seoo-allo-yohim bane 16B-carboxylic acid ester and subsequent solvolysis of a resulting A -l8-organic sulfonyloxy-allo-yohimbene IGfi-carboxylic acid ester, or a salt thereof, with an alcohol to yield the desired starting material, i.e. the 13 -18- etherified hydroxy-rallo-yohimbene l6fl-carboxylic acid esters. Ring closure (preferably with phosphorus oxychloride) and alcoholysis (preferably in the presence of an organic amine) are carried out according to methods described in detail hereinbefore,

'Ilhe A -l'8-etherified hydroxy-allo-yohimbene l6fi-carboxylic acid esters or salts thereof used as the starting materials in the above procedure may also be prepared, for example, by etherifying in a A -l8-hydroxy-alloyohimbene 16,8-carboxylic acid ester or a salt thereof, the free hydroxyl group, and, if desired, carrying out optional steps. The above etherification may be carried out according to previously described procedures, for example, by treatment with a diazo compound in the presence of a strong Lewis acid, e.g. fluoboric acid and the like, or any other etherification procedure capable of etherifying a secondary hydroxyl group.

The starting materials, which are used in the above procedure, are new and are intended to be included within the scope of the present invention. They are primarily those of the formulae:

2 in which R R R R R R and R have the previously given meaning, in which a double bond extends from the 3-position, or salts thereof.

Preferred groups of starting materials may be represented by the formulae:

in Which formulae the letters m, n, w, x, y and z and R have the previously given meaning, and in which a double bond extends from the 3-position, or salts of such compounds. Salts are especially those, in which the anion is derived from an inorganic, particularly a min eral, acid, such as one of those mentioned hereinabove, e.g. hydrohalic acids, e.g. hydrochloric, hydrobromic acid and the like, phosphoric acid, halogeno-phosphoric acids, e.g. chlorophosphoric acid and the like, or perchloric acid or any other suitable inorganic acid, as Well as organic acids, e.g. acetic acid and the like. These compounds are represented, for example, by lower alkyl 18- O-lower alkyl-3-dehydro-reserpates, in which lower alkyl has from one to seven carbon atoms, especially by the methyl 18-O-lower alkyl-3-dehydro-reserpates, in which lower alkyl has from one to three carbon atoms, and by the lower alkoxy-lower alkyl 18-epi-O-lower alkoxylower alkyl-3-dehydro-reserpates, in which lower alkyl has from two to three carbon atoms and separates lower 23 alkoxy having from one to four carbon atoms, from the l6B-carboxyl group and the 18a-oxygen atom, respectively by from two to three carbon atoms, or salts thereof.

In the previously mentioned methods for the preparation of the starting materials, new and important intermediates are being formed, which are intended to be included within the scope of this invention. Particularly useful are the IS-etherified hydroxy-3-oxo-2,3-seco-alloyohimbane 16,8-carboxylic acid esters, particularly those having one of the formulae:

in which R R R R R R and R have the previously given meaning.

Preferred groups of these intermediates are represented by the formulae:

in which the letters m, n, w, x, y and z, and R have the previously given meaning. These compounds are represented by lower alkyl 18-O-lower alkyl-3-oxo-2,3- seco-reserpates, in which lower alkyl has from one to seven carbon atoms, especially by the methyl 18-O- lower alkyl-3-oxo-2,3-seco-reserpates, in which lower alkyl has from one to three carbon atoms, by lower alkyl 18-epi-O-lower alkyl-3-oxo-2,3-seco-reserpates, in which lower alkyl has from one to seven carbon atoms, especially by the methyl IS-epi-O-lower alkyl-3-oxo-2,3- seco-reserpates, in which lower alkyl has from one to three carbon atoms, and by lower alkoxy-lower alkyl 18- epi O lower alkoxy lower alkyl 3- xo-2,3-seco-reserpates, in which lower alkyl has from two to three carbon atoms and separates lower alkoxy from the 16fi-carboxyl group and the 18a-oxygen atom, respectively, by from two to three carbon atoms.

The compounds of the present invention, as well as the starting materials and intermediates used in their formation, may be present in the form of mixtures of racemates, single racemates or antipodes.

Mixtures of racemates of final products or starting materials may be separated into the single racemates on the basis of physico-chemical diflerences, for example, by fractionated crystallization and the like.

Racemates of intermediates and final products may be resolved into antipodes. Racemates of final products or intermediates, forming acid addition salts, may be re solved, for example, by treating a solution of the free racemic base in a suitable inert solvent with one of the optically active forms of an acid containing an asymmetric carbon atom, or a solution thereof. Especially useful as optically active forms of salt-forming acids having an asymmetric carbon atom are D- and L-tartaric acid, as well as the optically active forms of di-o-toluyl-tartaric, malic, mandelic, camphor-lO-sulfonic, quinic acid and the like. A salt may then be isolated, which is formed by the optically active acid with one of the optically active forms of the base. The optically active forms may also be obtained by resolving racemates using biochemical methods. From an optically active salt, the free and optically active compounds may be obtained according to known methods used for the conversion of a salt into a free compound, for example, as outlined hereinbelow. A resulting optically active base amy be converted into an acid addition salt with one of the acids mentioned hereinbefore, or into an N-oxide or an acid addition salt of an N-oxide thereof, as shown hereinbelow.

The compounds of this invention or the N-oxides thereof may be obtained in the form of the free bases or as the salts thereof. A salt, including a salt of an N-oxide, may be converted into the free base, for example, by reacting the former with a basic reagent, such as, for example, aqueous ammonia, silver oxide and the like, or an ion exchange resin. A free base or the N-oxide thereof may be converted into the therapeutically useful acid addition salts thereof by treating it with one of the inorganic or organic acids mentioned hereinbefore; the reaction may be carried out, for example, by treating a solution of the free base in a suitable inert solvent with the acid or a solution thereof and isolating the resulting salt. The salts may also be obtained as the hemihydrates, monohydrates, sesquihydrates or polyhydrates depending on the conditions used in the formation of the salts.

N-oxides of the compounds of the present invention may be formed according to known methods; for example, a resulting compound, preferably a solution thereof in an inert solvent, may be reacted with an N-oxidizing reagent, such as, for example, hydrogen peroxide, ozone, persulfuric acid, or more especially, an organic peracid, such as an organic percarboxylic acid, e.g. peracetic, perbenzoic, monoperphthalic acid and the like, or a persulfonic acid, e.g. p-toluene persulfonic acid and the like. Inert solvents used in the preparation of the N-oxides are, for example, halogenated lower-alkanes, e.g. methylene chloride, chloroform, ethylene chloride and the like, lower alkanols, e.g. methanol, ethanol and the like, or any other suitable solvent. In the N-oxidation reaction an excess of the oxidation reagent and/ or an increase in temperature should be avoided in order to prevent oxidative degradation.

The invention also comprises any modification of the process wherein a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining step(s) of the process is (are) carried out. It also includes any new intermediates, which may be formed in one of the procedures outlined hereinbefore.

In the process of this invention such starting materials are preferably used which lead to final products mentioned in the beginning as preferred embodiments of the invention.

This is a continuation-in-part application of our application Serial No. 73,494, filed December 5, 1960, which in turn is a continuation-in-part application of our application Serial No. 46,875, now abandoned, filed August 2, 1960, which in turn is a continuation-in-part applicacation Serial No. 37,097, filed June 20, 1960, which in turn is a continuation-in-part application of our application Serial No. 837,357, now abandoned, filed September 1, 1959, which in turn is a continuation-in-part application of our application Serial No. 830,187, now abandoned, filed July 29, 1959. The present application is also a continuation-in-part application of our application Serial No. 73,490, now abandoned, filed December 5, 1960, which in turn is a continuation-in-part application of our application Serial No. 46,911, now abandoned, filed August 2, 1960. The present application is also a continuation-in-part application of our application Serial No. 84,519 now abandoned filed January 24 1961 which n turn is a continuation-in-part application of our abovementioned application Serial No. 73490 filed December 1960.

The following examples illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees centigrade.

Example 1 To a solution of 2.48 g. of methyl reserpate in 400 ml. of methylene chloride maintained at to is added 66 m1. of a fluoboric acid solution while stirring. (The latter is prepared as follows: Commercially available fifty percent aqueous fluoboric acid is concentrated by partial evaporation under reduced pressure to an approximately 14 N solution, determined by titration with a standard sodium hydroxide solution. A stock solution of approximately 0.1 N strength is prepared by dissolving 1 ml. of the concentrated fluoboric acid in a mixture of 110 ml. of absolute ether and 30 ml. of methylene chloride.) A small precipitate forms during the addition, which represents, probably, a salt of methyl reserpate with the acid.

A solution of diazomethane in methylene chloride (69 ml. of an 0.348 N solution) is added to the stirred reaction mixture over a period of about five minutes; during the addition the temperature is maintained at about '-10. The previously mentioned precipitate dissolves again. An additional 1 ml. of the stock solution is stirred for a few more minutes. 2 ml. of glacial acetic acid is added with the intent to destroy any excess of diazomethane.

The solution is washed twice with five percent aqueous sodium carbonate and once with saturated aqueous sodium chloride, the organic layer is dried over anhydrous sodium sulfate and evaporated under reduced pressure, whereupon 2.24 g. of a tan, solid material can be recovered, which is purified as follows: As much as possible of the residue is dissolved in 50 to 60 ml. of benzene at room temperature; the undissolved material is filtered off. The filtrate is chromatographed on about 40 g. of aluminum oxide (Woelm, neutral, activity I); the desired methyl IS-O-methyl-rescrpate is eluted with benzene, containing 0.2 percent of methanol. The oily, yellow solid is washed with cold ether and recrystallized from a 1:3-mixture of benzene and cyclohexane, using charcoal as a decolorizing agent, M.P. 228-231 (with decomposition) The purification step may also be carried out as follows: 7.5 g. of benzene-soluble material, obtained from the tan, solid product, is dissolved in ml. of benzene and placed on a column containing 240 g. of aluminum oxide (Woelm, neutral activity II-III). The column is washed with about 500 ml. of benzene, and subsequently with about 3,000 ml. of methylene chloride and about 2,000 ml. of methylene chloride containing 0.5 percent of methanol. The fractions obtained with methylene chloride and the first fractions eluted with the methylene chloride-methanol mixture are combined after evaporation of the solvent, and the residue is recrystallized using a 1:3-mixture of benzene and cyclohexane and charcoal as an adsorbent. The resulting, pure methyl 18-0-methylreserpate of the formula:

n 1 o H melts at 235-237, [oc] =l11 (in chloroform) and is identical with the above-described product.

Example 2 Example 3 A solution of 4.25 g. of n-propyl reserpate and ml. of the stock fluoboric acid solution described in Example l is treated with about five to six times the theoretical amount of a diazomethane solution in methylene chloride at 10. The reaction mixture is worked up as shown in Example 1; the n-propyl l8-O-methylreserpate melts at 164-165 after recrystallization from a 1:4-mixture of benzene and cyclohexane, [a] =-93 (chloroform); yield: 0.25 g.

n-Propyl 18-O-ethyl-reserpate may be prepared, for example, by reacting n-propyl reserpate with n-diazoethane in the presence of fiuoboric acid.

The starting material may be prepared as follows: Gaseous n-diazopropane is distilled from its ether solution into a suspension of 20 g. of reserpic acid in a 1:1-mixture of chloroform and ethanol. Any excess of n-diazopropane is decomposed with acetic acid, the solvents are evaporated under reduced pressure and the residue is poured into 800 ml. of water containing 20 ml. of concentrated aqueous ammonia. A white crystalline precipitate is obtained, which is washed with water to yield the n-propyl reserpate, M.P. 164-166".

Example 4 By replacing in Example 1 the methyl reserpate by 2.56 g. of ethyl reserpate and treating a mixture of the latter and a fluoboric acid preparation in methylene chloride with a diazomethane solution as shown in Example 1, the desired ethyl 18-O-methyl-reserpate can be obtained.

When treated with other lower diazo-alkanes, e.g. diazoethane, n-diazopropane, n-diazobutane and the like, according to the above procedure, ethyl reserpate yields other ethyl 18-O-lower alkyl-reserpates, such as ethyl l8-O-ethyl-reserpate, ethyl l8-O-n-propyl-reserpate, ethyl IS-O-n-butyl-reserpate and the like.

Example 5 Treatment of a solution of 2.67 g. of isopropyl reserpate and 66 ml. of the standard fluoboric acid preparation in methylene chloride with a diazomethane solution in methylene chloride at below -10 according to the procedure of Example 1, results in the formation of isopropyl l8-O-methyl-reserpate.

Upon treatment of isopropyl reserpate with n-diazopropane in the presence of fluoboric acid, isopropyl 18-O- n-propyl-reserpate is formed.

The starting material used in the above reaction may be prepared as follows: A mixture of 10 g. of methyl reserpate, 500 ml. of isopropanol and,20 drops of benzyl trimethyl ammonium hydroxide is refluxed for 2 /2 hours. After standing at room temperature for several hours, a white precipitate (needles) is formed, which is removed by filtration. The filtrate is evaporated to dryness, the foamy residue is taken up in 500 ml. of water containing 5 ml. of concentrated aqueous ammonia. The aqueous mixture is extracted with methylene chloride, the organic solvent is passed through a column containing a diatomaceous earth preparation and is then evaporated to dryness under reduced pressure. The residue is crystallized by the addition of diethyl ether, the crystalline material is filtered off, dried and identified as isopropyl reserpate, M.P. 214-216".

Other lower alkyl 18-O-methyl-reserpates, which may be prepared according to the aforementioned procedures are, for example, n-butyl 18-O-methyl-reserpate, n-butyl 18-O-ethyl-reserpate, isobutyl 18-O-methyl-reserpate, isopentyl IS-O-methyl-reserpate, n-hexyl 18-O-methyl-reserpate and the like. The starting materials used for the preparation of the above compounds are known or may be obtained according to methods used for the known compounds, particularly by treatment of reserpic acid with lower diazo-alkanes; isobutyl reserpate melts at 145-148 and isopentyl reserpate at 135-138", whereas n-hexyl reserpate has a melting point of 117-118.

Example 6 To a solution of 1.5 g. of methyl 18-O-methyl-reserpate in 25 ml. of acetone is added dropwise concentrated hydrochloric acid while stirring. The addition is carried out at room temperature and is interrupted after the solution becomes acidic to Congo red test paper. Crystallization occurs upon scratching, the crystalline material is tered off and washed with cold acetone. 1.5 g. of the methyl 18-O-methyl-reserpate hydrochloride is obtained, M.P. 237-242 (with decomposition).

Example 7 To a vigorously stirred solution of 5.0 g. of methyl deserpidate in 800 ml. of methylene chloride, is added a mixture of 158 ml. of diethylether, 43 ml. of methylene chloride and 1.4 ml. of concentrated aqueous fluoboric acid. The solution is then cooled to 11 in an ice-salt bath, and 324 ml. of a solution of diazomethane in methylene chloride is added in such manner that the ratio of diazomethane to methylene deserpidate is 6:1. During the addition the tempenature is kept between 7.5 and 11; stirring is continued for an additional twenty minutes and is then allowed to stand while cooling. After 1 /2 hours, the reaction mixture is washed with 850 ml. of a percent aqueous sodium carbonate solution and 350 ml. of a saturated aqueous sodium chloride solution, and the aqueous washes are extracted with methylene chloride, the organic extract is combined with the or ganic reaction solution, and the combined organic solutions are dried over sodium sulfate for 45 minutes. The organic solvent is evaporated, the residue is dissolved in 50 ml. of warm benzene, the insoluble material is filtered off and the filtrate is placed on a column containing 150 g. of aluminum oxide (activity II-III, neutral). The following fractions are collected: 500 ml. of benzene (fraction 1), 3000 ml. of methylene chloride (fractions 2 to 7 at 500 ml. each), 3000 ml. of methylene chloride, containing 0.5 percent of methanol (fractions 8 to 13 at 500 ml. each), 1500 ml. of methanol. Fractions 8 to 13 are combined and recrystallized from diethylether to yield 0.1 g. of methyl 18-O-methyl-deserpidate, M.P. 114-115 C.; [oc] =137 (chloroform).

Compounds, such as ethyl 18-O-methyl-deserpidate, ethyl 18-0-ethyl-deserpidate, ethyl l8-O-n-propyl-deserpidate, n-propyl 18-O-methyldeserpidate, n-propyl 18-O- ethyl-deserpidate, isopropyl 18-O-methyl-deserpidate, isopropyl 18-O-n-butyl-deserpidate, n-butyl 18-O-methyl-deserpidate, secondary butyl 18-O-methyl-deserpidate, npentyl 18-O-methyl-deserpidate, methyl 18-O-ethyl-deserpidate, methyl 18-O-propyl-deserpidate, methyl 18-O-isopropyl-deserpidate, methyl l8-n-butyl-deserpidate, methyl 18-O-secondary butyl-deserpidate and the like, are formed upon treatment of the corresponding lower alkyl deserpidates with lower diazo-alkanes according to the procedure of Example 1, or according to one of the other procedures previously described.

Example 8 By reacting a solution of 0.92 g. of Z-methoxyethyl reserpate and 22 ml. of the standard fluoboric acid preparation in methylene chloride with diazomethane as shown in Example 1, the desired 2-methoxyethyl 18-O-methylreserpate can be formed.

The starting material may be prepared as follows: To a mixture of 226 g. of a 33 percent aqueous solution of 2-methoxy-ethylamine and 150 ml. of diethyl ether, kept at 5 to 10 in an ice bath, is added dropwise 54 g. of ethyl chloroformate. g. of a cold 40 percent aqueous solution of sodium hydroxide and a second portion of 54 g. of ethyl chloroformate are given to the mixture, which is stirred for one hour. The ether layer is separated, the aqueous phase is extracted with 100 ml. of diethyl ether, and the two ether solutions are combined and dried over potassium carbonate. The solvent is evaporated under reduced pressure and the ethyl N-(2- methoxyethyl)-carbamate is distilled at -106/l7 to 20 mm.

To a solution of 33 g. of ethyl N-(2-methoxyethyl)- carbamate in 200 ml. of diethyl ether are added 25 g. of cracked ice and a solution of 81 g. of sodium nitrite in ml. of water. While keeping the temperature below 15, g. of 35 percent aqueous nitric acid is added carefully over a period of one hour. The ether layer is separated, washed with water and aqueous potassium carbonate and then dried over potassium carbonate. The residue, obtained after evaporation of the solvent under reduced pressure, represents the ethyl N-(Z-methoxyethyl)-N-nitroso-carbamate, which is used Without further purification.

A gently refluxing solution of 5 g. of potassium hydroxide in 15 g. of methanol and 150 ml. of diethyl ether is treated with a solution of 15.5 g. of ethyl N-(2- methoxyethyl)-N-nitroso-carbamate in 50 ml. of diethylether, which is added dropwise over a period of one hour. After refluxing for 5 minutes, 100 ml. of water is added and the yellow ether solution, containing the 2- methoxy-diazoethane, is separated.

The above ether solution of 2-methoxy-diazoethane is reacted with small portions of a slurry of reserpic acid in methanol until no further reaction can be observed.

A few drops of acetic acid are added, the solution is evaporated under reduced pressure and the residual oil is dissolved in ethyl acetate. Upon addition of petroleum ether a precipitate is formed, which is filtered ofil, dissolved in methylene chloride, which solution is washed with aqueous ammonia and filtered through a small column containing a diatomaceous earth. The residue, obtained after evaporation of the solvent, is crystallized from ethyl acetate to yield the 2-methoxyethyl reserpate, M.P. l83185.

Other lower alkoxy-lower alkyl 18-O-lower alkyl-reserpates and lower alkoxy-lower alkyl-deserpidates, in which lower alkoxy is separated from the carboxyl group by from two to three carbon atoms, which may be prepared according to the previously given procedure by replacing the starting material by other intermediates are, for example, 2-ethoxyethyl 18-O-methyl-reserpate, 2-ethoxyethyl 18-O-n-propyl-reserpate, 2-n-propyloxyethyl 18-O-methylreserpate, 2-isopropyloxyethyl 18-O-methyl-reserpate, 3- methoxypropyl l8-O-methyl-reserpate, 2-methoxypropyl l8-O-methyl-reserpate, Z-methoxyethyl l8-O-ethyl-reserpate, 2-methoxyethyl IS-O-n-propyl-reserpate, Z-methoxyethyl 18-O-methyl-deserpidate, Z-methoxyethyl 18-0- ethyl-deserpidate, 2-ethoxyethyl 18-O-methyl-deserpidate and the like.

Other compounds having a lower alkoxy-lower alkyl esterified carboxyl group, and which may be prepared according to one of the previously described methods,

are, for example, lower alkoxy-lower alkyl 18-O-lower alkoxy-lower alkyl-reserpates, in which lower alkoxy is separated from the 16-,carboxyl group and the 18-oxygen atom, respectively, by from two to three carbon atoms,

e.g. Z-methoxyethyl 18-O-(2-methoxyethyl)-reserpate, 2- methoxyethyl 18-0-(2 ethoxyethyl)-reserpate, 2 methoxyethyl 18-0-(Z-methoxypropyl)-reserpate, Z-methoxyethyl 18-0-(2-isopropyloxyethyl)-reserpate, 2 -methoxyethyl 18-0-(2 methoxypropyl) -reserpate, 2 ethoxyethyl 18-O-(2-rnethoxyethy1)-reserpate, 2-ethoxyethyl 18-O-(2- ethoxyethyl)-reserpate, 2-ethoxyethyl 18-0-(3-methoxypropyl)-reserpate, 2-n-propyloxyethyl 18-O-(2-methoxyethyl)reserpate, 2 isopropyloxyethyl 18 O-(2 ethoxyethyl)-reserpate, 2 methoxypropyl l8 O-(2 methoxyethyl)-reserpate, Z-methoxypropyl 18-O-(2-ethoxyethyl) reserpate, 3-methoxypropyl 18-O-(2-methoxyethyl)-reserpate, 3-ethoxypropyl 18-0-(3 -methoxypropyl)-reserpate and the like, lower alkoxy-lower alkyl 18-O-lower alkoxylower alkyl-lO-methoxy-deserpidates, in which lower alkoxy is separated from the 16-carboxyl group and the 18- oxygen atom, respectively, by from two to three carbon atoms, e.g. Z-methoxyethyl lO-methoxy-l 8-O-(2-methoxyethyl)-deserpidates, 2 methoxyethyl 18 O-(2 ethoxyethyl)-10-methoxy-deserpidate, Z-methoxyethyl 18-0-(2- ethoxypropyl)-10-methoxy-deserpidate, 2 methoxyethyl 10-methoxy-l8-O-( Z-methoxypropyl) -deserpidate, Z-ethoxyethyl IO-methoxy-lS-O-(Z-methoxyethyl)-deserpidate, 2-methoxypropyl 10-methoxy-IS-O-(Z-methoxyethyl)-deserpidate, 3-methoxypropyl IO-methoxy-l8-O-(2-methoxy- 'ethyD-deserpidate and the like, lower alkoxy-lower alkyl 18-O-lower alkoxy-lower alkyl-deserpidates, in which 10W- er alkoxy is separated from the 16-carboxyl group and the l8-oxygen atom, respectively, by from two to three carbon atoms, Z-methoxyethyl 18-O-(2-methoxyethyl)- deserpidate, Z-methoxyethyl 18-0-(2-ethoxyethyl)-deserpidate, 2-methoxyethyl 18-0-(2-methoxypropyl)-deserpidate, Z-methoxyethyl 18-0-(3 -methoxypropyl)-deserpi date, Z-methoxyethyl 18-O-(3-ethoxypropyl)-deserpidate, 2-ethoxyethyl 18-0-(2-methoxyethyl)-deserpidate, 2-ethoxyethyl l8-O-(2 ethoxyethyl)-deserpidate, 2 n-propyloxyethyl 18-O-(2-methoxyethyl)-deserpidate, 2 n-butyloxyethyl l8-O-(2-methoxyethyl)-deserpidate, 2-methoxypropyl 18-0-(2 methoxyethyl)-deserpidate, 2 methoxypropyl l8-O-(2-ethoxyethyl)-deserpidate, 3-meth0xypropyl 18-O-(2-methoxyethyl)-deserpidate, 3 -ethoxypropyl l8-O-(2-methoxyethyl)-deserpidate and the like, and acid addition salts thereof.

Example 9 To a solution of 4.55 g. of methyl reserpate in 730 ml. of methylene chloride is given 121 ml. of the concentrated fluoboric acid solution described in Example 1. ml. of an 0.3 molar solution of n-diazobutane is added, and the reaction mixture is treated and worked up as shown in Example 1. The resulting methyl l8-O-nbutyl-reserpate is recrystallized from a mixture of benzene and cyclohexane, MP. 219-221 (with decomposition).

In the above example, n-diazobutane may be replaced by other lower diazo-alkanes, e.g. n-diazopropane, diazoisopropane, diazo-isobutane, n-diazopentane and the like; upon reacting these reagents with methyl reserpate in the presence of fiuoboric acid as shown hereinabove, methyl 18-O-n-propyl-reserpate, methyl 18-O-isopropylreserpate, methyl 18-O-isobutyl-reserpate, methyl 18-0- n-pentyl-reserpate and the like, are formed and may be converted into their acid addition salts, e.g. hydrochloride and the like as shown in Example 6.

Example 10 A solution of 1.25 g. of methyl lO-methoxy-deserpidate and about 35 ml. of the fluoboric acid preparation described in Example 1 in methylene chloride, when treated with a diazoethane solution in methylene chloride at a temperature below 10 according to the method outlined in Example 1, yields the desired methyl lO-methoxy- 18-O-ethyl-deserpidate.

Upon treatment with hydrochloric acid according to the method described in Example 6, the methyl 10-methoxy-l8-O-ethyl-deserpidate hydrochloride is formed.

Other lower alkyl 18-O-lower alkyl-lO-methoxy-desen pidates, such as, for example, methyl 18-O-n-propyl-10- methoxy deserpidate, methyl lO-methoxy-lS-O-n-butyldeserpidate, ethyl 10-methoxy-lS-O-methyl-deserpidate, npropyl IO-methoxy-lS-O-methyl-deserpidate, isopropyl 10- methoxy-l8-O-methyl-deserpidate and the like, or the salts thereof, are prepared by treating appropriate lower alkyl IO-methoxy-deserpidates with the desired lower diazo-alkanes according to the method described in detail in Example 1.

Other 18,6-etherified hydroxy-3-epi-allo-yohimbane 16B- carboxylic acid esters, which may be prepared according to one of the above-described methods by selecting the appropriate starting materials, are, for example, lower alkyl 18-O-lower alkyl-S-methyl-reserpates, e.g. methyl S-methyl-lS O-methyl-reserpate, methyl l8 O-ethyl-S- methyl-reserpate, ethyl S-methyl l8 O-methyl-reserpate and the like, lower alkyl 18-O-lower alkyl-S-methyl-deserpidates, e.g. methyl S-methyl- IS-O-methyl-deserpidate, methyl 5 methyl 18 O-n-propyl-deserpidate, ethyl 5- methyl-l8-O-methyl-deserpidate and theilike, lower alkyl l8-O-lower alkyl-6-methyl-reserpates, e.g. methyl 6-methyl-l8-O-methyl-reserpate, methyl 18-O-ethyl-6-methyl-reserpate, methyl 18-O-n-butyl-fi-methyl-reserpate, ethyl 6- methyl-lS-O-methyl-reserpate, n-propyl 6-methyl 18 O- methyl-reserpate, lower alkyl 18-O-lower alkyl-6-methyldeserpidates, e.g. methyl 6-methyl-18-O-methyl-deserpidate, methyl 6-methyl-18-O-n-propyl-deserpidate, ethyl 6- methyl-lS-O-methyI-reserpate and the like, lower alkyl 18-O-lower alkyl-9-methyl-deserpidates, e.g. methyl 9- methyl-lS-O-methyl-deserpidate, methyl 18 O ethyl 9- methyl-deserpidate, methyl l8-O-n-butyl-9-methyl-deserpidate, ethyl 9-methyl-IS-O-methyl-deserpidate, n-propyl 9-methyl-l8-O-methyl-deserpidate and the like, lower alkyl 18-O-lower alkyl-ltl-methyl-deserpidates, e.g. methyl IO-methyl-l8-O-methyl-deserpidate, methyl 18 O-ethyl- 31 O-methyl'deserpidate, methyl 18-O-ethyl-9-methoXy-deserpidate, methyl 9-methoxy-18 O-n-propyl-deserpidate, ethyl 9-methoXy-lS-O-methyI-deserpidate and the like, lower alkoxy l8-O-lower alkyl-10-methoxy-reserpates, e.g. methyl IO-methoxy-lS-O-methyl-reserpate, methyl 18-0- ethyl-IO-methoxy-reserpate, ethyl IO-methoxy-lS-O-methyl-reserpate, ethyl IG-methoxy 18 O-n-propyl-reserpate and the like, lower alkyl lO-ethoxy-lS-O-lower alkyl-deserpidates, e.g. methyl 10-ethoxy 18 O-methyl-deserpidate, methyl IO-ethoxy-18-0-n-propyl-deserpidate, n-pro pyl IO-ethoxy-l8-O-methyl-deserpidate and the like, lower alkyl 18 O-lower alkyl 12 methoxy-deserpidates, e.g. methyl l2-methoxy-IS-O-methyl-deserpidate, methyl 18- O-n-butyl-12-methoxy deserpidate, ethyl 12-methoxy-18- O-methyl-deserpidate, n-propyl 12-methoXy-18-O-methyldeserpidate and the like, lower alkyl 11-ethoxy-18-O- lower alkyl-deserpidates, e.g. methyl ll-ethoxy 18 O- methyl-deserpidate, methyl 1l-ethoxy-lS-O-ethyl-deserpidate, ethyl 1l-ethoxy-18-O-methyl-deserpidate and the like, lower alkyl 18-O-lower alkyl-1l-n-propyloxy-deserpidates, e.g. methyl 18-O-methyl-1l-n-propyloxy-deserpidate, methyl l8-O-n-propyl-11 -n-propyloxy-deserpidate, ethyl IS-O-methyl-l1-n-propyloxy-deserpidate, ethyl 18- O-methyl-l1-n-propyloXy-deserpidate and the like, lower alkyl 1l-isopropyloxy-l8-O-lower alkyl-deserpidates, e.g. methyl 11-isopropyloxy-18-O-methyl-deserpidate, methyl 18-O-ethyl-ll-isopropyloxy-deserpidate, ethyl ll -isopropyloxy-lS-O-methyl-deserpidate, n-butyl ll-isopropyloxy- IS-O-methyI-deserpidate and the like, lower alkyl ll-n-butyloxy-18-O-lower alkyl-deserpidates, e.g. methyl ll-n-butyloxy-18-O-methyl-deserpidate, methyl ll-n-butyloxy-IS- O-ethyl-deserpidate, ethyl 1l-n-butyloxy-lS-O-methyl-deserpidate and the like, lower alkyl 9,10-dimethoxy-18-O- lower alkyl-reserpates, e.g. methyl 9,10-dimethoxy-18-O- methyl-reserpate, methyl 9,10-dimethoxy-18 O-ethyl-reserpate, methyl 9,10-dimethoxy-18-O-n-propyl-reserpate, ethyl 9,10-dimethoxy-l8-O-ethyl-reserpate, n-butyl 9,10- dimethoxy- 18 O-methyl-reserpate and the like, lower alkyl 18 O-lower alkyl 10,11 methylenedioxy-deserpidates, e.g. methyl 18-O-methyl-10,1l-methylenedioxy-deserpidate, methyl 18-O-ethyl-10,1l-methylenedioxy-deserpidate, ethyl 18-O-methyl-10,1l-methylenedioxy-deserpidate and the like, lower alkyl IO-benzyloxy-lS-O-lower alkyl-deserpidates, e.g. methyl 10-benzyloxy-18-O-methyldeserpidate, methyl 10-benzyloXy-l8-O-ethyl-deserpidate, ethyl IO-benzyloxy-lS-O-methyl-deserpidate, n-propyl 10- benzyloxy-IS-O-methyl-deserpidate and the like, lower alkyl ll-benzyloxy l8 O-lower alkyl-deserpidates, e.g. methyl ll-benzyloxy-18-O-methyl-deserpidate, methyl 11- benzyloxy-IS-O-ethyI-deserpidate, ethyl 11-benzyloXy-18- O-methyl-deserpidate and the like, lower alkyl 18-O-lower alkyl-10-methylmercapto-deserpidates, e.g. methyl 18-0- methyl l methylmercapto-deserpidate, methyl 18 O- ethyl -methylmercapto-deserpidate, methyl IO-methylmercapto-l8-O-n-propyl-deserpidate, ethyl 18-O-methyl- 10-methylmercapto-deserpidate and the like, lower alkyl 18-O-lower alkyl 11 methylmercapto-deserpidates, e.g. methyl 18 O-methyl 1 1 methylmercapto-deserpidate, methyl 18-O-ethyl-11-methylmercapto-deserpidate, ethyl 18-O-methyl-1l-methylmercapto-deserpidate, n-propyl 18- O-methyl-ll methylmercapto-deserpidate and the like, lower alkyl 1l-ethylmercapto-18O-lower alkyl-deserpidates, e.g. methyl 1l-ethylmercapto-18-O-methyl-deserpidate, methyl 1l-ethylmercapto-l8-O-n-propyl-deserpidate, ethyl ll-ethylmercapto-18-0-methyl-deserpidate, n-propyl 1l-ethylmercapto-lS-O-methyl-deserpidate and the like, lower alkyl 10-fluoro-18-O-lower alkyl-deserpidates, e.g. methyl 10-fluoro-IS-O-methyl-deserpidate, ethyl IO-fluoro- 18-O-methyl-deserpidate, ethyl l0-fiuoro-118-O-n-propyldeserpidate and the like, lower alkyl 11-flu0ro-18-O-lower aJkyl-deserpidates, e.g. methyl 11-fiu0ro-18-O-methyl-deserpidate, methyl 1l-fiuoro-lS-O-ethyl-deserpidate, ethyl ll-fluoro 18 O-methyl-deserpidate and the like, lower alkyl l0-chloro-18-O-lower alkyl-deserpidates, e.g. methyl IO-chloro-l8-O-methyl-deserpidate. methyl 10-chloro-18- 32 O-ethyl-deserpidate, methyl 10-chloro-18 O-n-propyl-deserpidate, ethyl 18-O-n-butyl-IO-chloro-deserpidate, isopropyl 10-chloro-18-O-methyl-deserpidate and the like, lower alkyl 9,12-dichloro-18-O-lower alkyl-deserpidates, e.g. methyl 9,12-dichloro-18-O-methyl-deserpidate, methyl 9,12-dichloro 18 O-n-propyl-deserpidate, ethyl 9,12-dichloro-18-O-ethyl-deserpidate and the like, lower alkyl 11,12-dichloro-18-O-lower alkyl-deserpidates, e.g. methyl 11,12-dichloro-l8-O-methyldeserpidate, methyl 11,12-dichloro-l8-O-ethyl-deserpidate, ethyl 11,12-dichloro-l8-O- n-propyl-deserpidate and the like, lower alkyl IO-chloro- 18-O-lower alkyl-reserpates, e.g. methyl 10-chloro-18-O- methyl-reserpate, methyl 10-chloro- 18-O-n-propyl-reserpate, ethyl 10-chloro-18-O-methyl-reserpate and the like, lower alkyl 10-bromo-l8-O-lower alkyl-reserpates, e.g. methyl l0 bromo 18 O-methyl-reserpate, methyl 10- bromo 18 O ethyl reserpate, methyl 10 bromo- 18 O n butyl reserpate, ethyl 10 bromo 18 O- methyl-reserpate, ethyl 10-bromo 18 O-ethyl-reserpate, and the like, lower alkyl 17ot-desmethoxy-17a-ethoxy-18- O-lower alkyl-reserpates, e.g. methyl 17a-desmethoxy-17aethoxy 18 O-methyl-reserpate, methyl l7a-desmethoxy- 17a-ethoxy-18-O-ethyl-reserpate, methyl 17a-desmethoxyl7oc-ethoxy 18 O-n-propyl-reserpate, n-propyl 17a-desmethoxy-17u-ethoxy18-O-methyl-reserpate and the like, lower alkyl 17a-desmethoxy-18-O-lower alkyl-17a-n-propyloxy-reserpates, e.g. methyl l7a-desmethoxy 18 O- methyl-l7u-n-propyloxy-reserpate, ethyl 17m-desmethoxy- 18-O-methyl-l7a-n-propyloxy-reserpate and the like, lower alkyl 17a-desmethoxy-17u-isopropyloxy-18-O-lower alkyl-reserpates, e.g. methyl 17a-desmethoxy-l7a-isopropyloxy-l8-O-methyl-reserpate, methyl 17u-desmethoxy-18-O- ethyl-17a-isopropyloxy-reserpate and the like, lower alkyl 17a-desmethoxy 17u-ethoxy 18 O-lower alkyl-deserpidates, e.g. methyl l7a-desmethoxy-l7u-ethoxy-18-O-methyl-deserpidate, methyl 17a-desmethoxy-17a-ethoxy-18-O- ethyl-deserpidate, methyl 17a-desmethoxy-17a-ethoxy-18- O-isobutyl-deserpidate, ethyl l7a-desmethoxy-l7a-ethoxy- 18-O-methyl-deserpidate, ethyl 17a-desmethoxy-17a-ethoxy-l8-O-ethyl-deserpidate, and the like, lower alkyl 17ozcyano-17u-desmethoxy-l8 O-lower alkyl-reserpates, e.g. methyl 17u-cyano-17a-desmethoxy 18 O-methyl-reserpate, methyl 17a-cyano-l7a-desmethoxy-1S-O-ethyl-reserpate, methyl 17x-cyano-17a-desmethoxy-1S-O-n-propyl-reserpate, n-propyl 17u-cyano-17a-desmethoxy-18-O-methyl-reserpate and the like, lower alkyl 17u-cyano-17adesmethoxy 18 O-lower alkyl-deserpidates, e.g. methyl 17cc cyano desmethoxy IS-O-methyl-deserpidate, methyl 17 a-cyano-17a-desmethoxy 18 O-ethyl-deserpidate, ethyl l7ot-cyano-l7a-desmethoxy-l8-O-methyl-deserpidate and the like, N,N-di-lower alkyl-amino-lower alkyl ,l8-O-lower alkyl-reserpates, in which the N,N-di-lower alkyl-amino group is separated from the carboxyl group by from two to three carbon atoms, e.g. 2-N,N-dimethylaminoethyl 18-O-methyl-reserpate, 2-N,N-dimethylaminoethyl 18-O-ethyl-reserpate, 2-N,N-diethylaminoethyl 18- O-methyl-reserpate, 3 N,N-dimethylaminopropyl 18 O- methyl-reserpate and the like, N,Ndi-lower alkyl-aminolower alkyl 18-O-lower alkyl-deserpidates, in which the N,N-di-lower alkyl-amino group is separated from the carboxyl group by from two to three carbon atoms, e.g. 2-N,N-dimethylaminoethyl 18-O-methyl-deserpidate, 2-N, N-dimethylaminoethyl 18-O-ethyl-deserpidate, 2-N,N-dimethylamino-propyl 18-O-methyl-deserpidate and the like, and pharmacologically acceptable acid addition salts thereof.

Example 11 To a solution of 1.2 g. of methyl l8-epi-reserpate in 400 ml. of methylene chloride is added 5 ml. of the stock fluoboric acid solution described in Example 1. The reaction mixture is kept at a temperature of about 10 and a solution of an excess of diazobutane in methylene chloride is added. The reaction mixture is worked up as shown in Example 1. and the resulting 33 methyl 18-epi-O-n-butyl-reserpate is obtained, which melts at 224-226 (decomposition).

The starting material used in the above reaction may be prepared as follows: To a solution of 10.0 g. of methyl reserpate in 70 ml. of pyridine is added 15.8 g. of 4- bromo-benzene sulfonyl chloride; the reaction mixture is allowed to stand at room temperature for 2 /2 days and is then poured into ice-water. The organic material is extracted with chloroform, the organic extract is Washed with a 5 percent aqueous sodium hydroxide solution and subsequently with water until a neutral reaction is obtained. The organic solution is evaporated to dryness, and the resulting methyl 18-O-(4-bromophenyl-sulfonyl)-reserpate is recrystallized from acetone, MP. 209- 212; yield: 5.64 g.

A mixture of 6.34 g. of methyl 18-O-(4-bromo-phenylsulfonyl)-reserpate, 100 ml. of water, 300 ml. of p-dioxane and 1.2 g. of N,N,N-triethylamine is heated on the steambath for 41 hours under an atmosphere of nitrogen. The organic solvent is evaporated under reduced pressure, during which operation a precipitate is formed, which is filtered oil and dissolved in methylene chloride. The resulting organic solution is extracted with several portions of 5 percent aqueous hydrochloric acid until the acidic extracts no longer give a precipitate on addition of ammonium hydroxide. The combined precipitates, resulting from the treatment of the acidic extracts with aqueous ammonia, are washed with water and dried to yield 2.73 g. of methyl 18-epi-reserpate monohydrate, M.P. 220222 (decomposition). Upon drying at 140 under reduced pressure, the above hydrate can be converted into the solvent-free methyl 18-epi-reserpate, M.P. 220- 222, [a] =8O.5 (in chloroform).

Example 12 A mixture of 1.9 g. of methyl l8-O-(4 b romo-phenyh sulfonyD-reserpate, 0.36 g. of N,N,N-triethylamine and 240 ml. of methanol is sealed in a thiclewalled hydrogenation bottle after squirting with nitrogen. The reaction mixture is heated on the steam bath for 21 hours; the light yellow solution is evaporated, the residue is extracted into methylene chloride, and the organic solution is washed with a 5 percent aqueous sodium carbonate solution and subsequently with a saturated aqueous sodium chloride solution, and is then dried and evaporated to yield a tan solid, which is muddled with diethyl ether. The latter is dissolved in a 1:2 mixture of benzene and cyclohexane, the solution is passed through charcoal, and the filtrate is evaporated to a small volume, whereupon crystallization occurs. The resulting methyl 18-epi-O- methyl-reserpate of the formula:

melts at 24l244 (with decomposition); yield: 0.86 g.

The starting material used in the above procedure may be prepared as shown in Example =1'1.

Example 13 To a solution of 6.35 g. of methyl 18-epi-O methylreserpate in 100 m1. of acetone is added a solution oat 1.4 ml. of concentrated hydrochloric acid in 16 m1. of acetone. A gel-like material precipitates immediately, which on scratching becomes crystalline. The mixture is chilled in an ice bath for thirty minutes, the solid material is filtered oil and washed with cold acetone to yield the desired methyl 1 8-epi-O-methyl-reserpate hydrochloride, MP. 239-242" (decomposition).

Example 14 A solution of 0.43 g. of methyl 18-O'-methylreserpate in 40 ml. of methylene chloride is cooled to 0, and, while stirring, 3 ml. of 0.339 M perbenzoic acid in chloroform is added over a period of seven minutes. The cold, pink solution is stirred for an additional fifteen minutes in an ice-bath, then extracted twice with a cold five percent aqueous sodium carbonate solution and washed with a saturated aqueous sodium chloride solution. The organic layer is separated, dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue is dissolved in methylene chloride, and the solution is placed on a column of aluminum oxide (W oelm, neutral, activity 11-111). The column is washed with methylene chloride and the product is eluted with methylene chloride containing one percent of methanol. The solvent is evaporated, and the residue is triturated with acetone to yield 0.11 g. of crystalline material, which is recrystallized by dissolving it in methylene chloride, adding acetone and evaporating most of the methylene chloride. The white, crystalline methyl 18-O-methyl-reserpate N-oxide melts at 238 with decomposition.

Upon treatment of the methyl 18-O-methyl-reserpate N-oxide with hydromloric acid as shown in Example 6, the desired IS-Omethyl-resenpate N-oxide hydrochloride can be prepared.

The methyl 1 S-O-ethyl-reserpate N-oxide may be prepared by reacting methyl l8-O-ethyl-reserpate with perbenzoic acid according to the procedure described hereinbefore; the resulting free compound may be converted into the methyl 18-O-ethyl-reserpate N-oxide hydrochloride by treatment with hydrochloric acid in an appropriate solvent, as, for example, described in Example 6.

Example 15 To a solution of 0.8 g. of benzyl reser'pate in ml. of methylene chloride is added 20 ml. of the standard fluoboric acid preparation (described in Example 1) and then an excess of diazomethane (using a methylene chloride solution of the reagent). The reaction mixture is kept at temperatures below 10 and is worked up according to the procedure of Example -1 to yield the desired benzyl 1'8-O-methyl-reserpate.

The benzyl 18-epi-O-methyl-reserpate may be obtained for example, by treating 'benzyl l8-O-(4-hromo-phenyl sulfonyl)reserpate with methanol in the presence of I-T,N,N-triethylamine according to the procedure described in Example 12.

Example 16 A solution of 2.58 g. of methyl 18-epi-reserpate monohydrate in 700 ml. of methylene chloride is cooled to -'l0 and 90 ml. of an 0.1 M stock solution of fluoboric acid is added. (The latter is prepared by concentrating commercial 50 percent fluo boric acid to a concentration of about '14 M and diluting the concentrate with the appropriate quantity of an 11:3-mixture of absolute diethyl ether and methylene chloride.) The turbid solution is cooled to 12 and ml. of an 0.265 M solution of diazomethane in methylene chloride is added over a. period of seven minutes and while stirring. The reaction mixture is stirred for an additional '15 minutes, a small amount of glacial acetic acid is added to destroy the excess of diazomethane, and the solution is then washed twice with 5 percent aqueous sodium carbonate and once with a saturated aqueous solution of sodium chloride. The organic layer is separated, dried over anhydrous sodium sulfiate and evaporated under reduced pressure. The residue contains about 20 to 30 percent of the desired methyl 1'8-epi-O-n1ethyl-reserpate. The identity of the product with the methyl l8-epi-Omethylreserpate, prepared according to the procedure of Example 12 is established paper chromato-graphically: The Rf-value of methyl 1S-epi-O-methyl-reserpate on paper impregnated with a 1:1-mixture of formarnide (adjusted to pH 5.6 with benzoic acid) and methanol, using chloroform as the mobile phase, is Rf=0.45, with chloroform containing percent pyridine as the mobile phase, Rf=0.80, and with a lzl-mixture of chloroform and benzene as the mobile phase, Rf=O.l5, as compared with Rf=0.13, Rf=O.55 and Rf=0.04 in the respective systems for methyl IS-epireserpate used as the starting material. I

Example 17 A mixture of 3.17 g. of methyl 18-O-(4-bromo-phenylsulfonyl)-reserpate, 0.6 g. of N,N,N tr iethylamine and 240 ml. of absolute ethanol is heated in a sealed vessel on the steam bath for five days while maintaining a nitrogen atmosphere and stirring. The solvent is evaporated under reduced pressure, the residue is dissolved in methylene chloride and the solution is washed twice with a five percent aqueous solution of sodium carbonate and once with a saturated aqueous solution of sodium chloride. The organic solution is dried, the solvent is evaporated, the residue is triturated with diethyl ether, and the organic solvent is evaporated to leave 2.0 1 g. of crude methyl 18- epi-Oethyl-reserpate of the formula:

The crude product is recrystallized several times from a mixture of benzene and cyclohexane and melts at 229- 230 (decomposition); [a] =27 (chloroform).

Example 18 To a solution of 0.88 g. of methyl 18-epi-O-ethyl-reserpate in ml. of acetone is added a solution of 0.2 ml. of concentrated hydrochloric acid in 2.2 ml. of acetone. A crystalline product is obtained on scratching; the slurry is chilled and the methyl IS-epi-O-ethyl-reserpate hydro chloride is obtained in white plates, which are filtered oil and washed with cold acetone, M.P. 233-235 (decomposition).

Example 19 A mixture of 5.56 g. of methyl l8-O-(4-bromo-phenylsulfonyl)-reserpate, 0.90 g. of N,N,N-triethylarnine and 250 ml. of n-propanol is refluxed in a nitrogen atmosphere for 95 hours. After evaporating the solvent the reaction mixture is worked up as shown in Example 17 to yield the desired methyl 18-epi-O-n-propyl-reserpate of the formula:

which melts at 223-225 (decomposition) after recrystallization from a mixture of benzene and cyclohexane; [a] =26 (chloroform).

Example A total of 0.91 g. of methyl l8-epi-O-n-propyl-reserpate is dissolved in ml. of 0.1 N aqueous hydrochloric acid; the solution is frozen and lyophilized to yield the semicrystalline methyl 18-epi-O-n-propyl-reserpate hydrochloride, which crystallizes as the dihydrate, M.P. 213- 223 (decomposition).

Example 21 A mixture of 5.56 g. of methyl 18-O-(4-bromo-phenylsulfonyD-reserpate, 0.9 g. of N,N,N-triethylamine and 240 ml. of isopropanol is heated for thirteen days in a ealed vesesl at 100 While stirring. The reaction mixture is worked up as shown in Example 17 to yield the methyl 18-epi-O-isopropyl-reserpate, which melts at 225- 229 (decomposition) after recrystallization from a mixture of benzene and cyclohexane; [a] =23 (chloroform).

The hydrochloride, which is prepared according to the lyophilization procedure of Example 20, crystallizes with 1 /2 moles of water, M.P. 224228 (decomposition).

Example 22 A mixture of 5.56 g. of methyl 18-O-(4-bromo-phenylsulfonyl)-reserpate, 0.9 g. of N,N,N-triethylamine and 333 ml. of n-butanol is refluxed under an atmosphere of nitrogen for 15 /2 hours. The reaction mixture is worked up according to the method described in Example 17 to yield the methyl 18-epi-O-n-butyl-reserpate, which melts at 224226 (decomposition) after recrystallizations from the mixture of benzene and cyclohexane; [a] =l8 (chloroform).

The hydrochloride, M.P. 220-225 (decomposition) is prepared according to the lyophilization procedure described in Example 20 and crystallizes with 1 moles of Water.

Example 23 A mixture of 3.17 g. of methyl l8-O-(4-bromo-phenylsulfonyl)-reserpate, 0.6 ml. of N,N,N-triethylamine and 10 ml. of benzyl alcohol is heated at 100 for four days while maintaining a nitrogen atmosphere. The benzyl alcohol is evaporated under reduced pressure, the residue is taken up in methylene chloride; which solution is washed with an aqueous solution of sodium carbonate and a saturated solution of sodium chloride, dried and then evaporated. The oily residue is crystallized by stirring with diethyl ether. The solid material is separated by filtration, is washed with diethyl ether and recrystallized from percent ethanol to yield methyl 18-epi-O-benzylreserpate, which melts at 225226 (decomposition) after recrystallization from a mixture of benzene and cyclohexane; [a] =+lZ (chloroform).

Example 24 A mixture of 4.75 g. of methyl 18-0-(4-bromo-phenylsulfonyl)reserpate, 0.9 g. of N,N,N-triethylamine, 50 ml. of ethylene glycol and 50 ml. of p-dioxane (purified by filtration through a column of aluminum oxide, basic, Woelm activity I) is heated at in a nitrogen atmosphere while stirring at 100 for a period of 4 /2 days. The dioxane is evaporated under reduced pressure, and the remaining solution is taken up in methylene chloride. The organic solution is washed several times with 300 ml. portions of dilute (about 3 percent) aqueous sodium carbonate, with water and with saturated aqueous sodium chloride. On evaporation of the solvents an amorphous residue which crystallizes upon stirring with diethyl ether. The solid material is filtered off, washed with diethyl ether and recrystallized from acetonitrile to yield the methyl 18 epi O-(Z-hydroxyethyl)-reserpate, M.P. 237239 (decomposition); [a] =-26 (chloroform).

The hydrochloride of methyl 18-epi-O-(2-hydroxyethyl)-reserpate, prepared according to the procedure of Example 18, melts at 220-226 (decomposition) and crystallizes from the acetone solution as the hemihydrate.

Example 25 chloride solution is triturated with diethyl ether, the solid material is filtered ofi, andwashed with diethyl ether to yield methyl 18-epi-O-n-pentyl-reserpate, M.P. 231-233 (decomposition); [a];, =15 (chloroform).

Example 26 0.97 g. of methyl 18-epi-O-n-pentyl-reserpate is dissolved as completely as possible in 100 ml. of 0.1 N aqueous hydrochloric acid, the insoluble material is filtered oif, and the solution is freeze-dried to yield methyl l8 epi-O-n-pentyl-reserpate hydrochloride, which melts at 222-224" (decomposition) and crystallizes with 1 /2 moles of water.

Example 27 A mixture of 4.75 g. of methyl l8-O-(4-bromo-phenylsulfonyl)-reserpate, 0.9 g. of N,N,N-triethylamine and 310 ml. of isobutanol is refluxed for four days; the reaction is worked as shown in Example 17 to yield the methyl 18-epi-O-isobutyl-reserpate, which melts at 234- 236 (decomposition); [a] =l8 (chloroform).

The hydrochloride is prepared according to the lyophilization procedure described in Example 20 and is obtained as the monohydrate, M.P. 215-224" (decomposition).

Example 28 A mixture of 2.0 g. of methyl IS-O-methylsulfonylreserpate, 0.5 g. of N,N,N-triethylamine and 120 ml. of methanol is placed in a pressure flask, which is then flushed with nitrogen and sealed. The mixture is heated on the steam bath for twenty days; the solvents are evaporated under reduced pressure and the residue is taken up in methylene chloride. The organic solution is washed twice with a five percent aqueous solution of sodium carbonate and once with a saturated aqueous sodium chloride solution, then filtered through a diatomaceous earth preparation and evaporated under reduced pressure. The residue is taken up in 25 ml. of hot benzene, the solution is filtered, the filtrate is clarified with charcoal and diluted with 75 ml. of cyclohexane and then cooled. 1.19 g. of crystalline methyl 1S-epi-O-methyl-reserpate, M.P. 230- 233 precipitates and is collected; the product is identical with the compound obtained according to the procedure of Example 12, [a] =37 (chloroform).

The starting material may be prepared by adding 2.12 g. of methane sulfonyl chloride and 45 ml. of pyridine to a solution of 6 g. of methyl reserpate in 105 ml. of pyridine while cooling in an ice bath, allowing the mixture to stand at room temperature for three days and diluting it with 750 ml. of a 2.5 percent aqueous sodium hydrogen carbonate solution. The resulting methyl 18-O-methylsulfonyl-reserpate is recrystallized from a mixture of methanol and methylene chloride, M.P. 244245; yield: 5.4 g.

Example 29 A mixture of 0.1 g. of methyl l8-O-(4-nitro-phenylsulfonyl)reserpate, 0.02 g. N,N,N-triethylamine and 25 ml. of methanol is heated at 100 in a sealed vessel for 17 /2 hours; the reaction mixture is worked up as shown in Example 17 to yield the methyl 18-epi-O-methylreserpate, M.P. 23924l (decomposition). The prodnot is identical with the compound described according to the procedure of Example 12.

The starting material is prepared as follows: A mixture of 4.14 g. of methyl reserpate, 5.2 g. of 4-nitro-benzene sulfonyl chloride and 17 ml. of pyridine is allowed to stand at room temperature for three days and is then poured into 200 ml. of ice-water. The aqueous mixture is extracted twice with methylene chloride, the organic extracts are washed with cold aqueous sodium bicarbonate and with saturated aqueous sodium chloride and then evaporated under reduced pressure after drying. The residue is dissolved in methylene chloride, the solution is filtered through a column containing a diatomaceous earth preparation and further elution with methylene choride yields the crude methyl l8-O-(4-nitro-phenyl- 32-8 sulfonyl)-reserpate. The pure compound melts at 202- 204 (decomposition) after recrystallization from acetonitrile.

Example 30 A mixture of 0.64 g. of methyl l8-epi-O-(4-bromophenyl-sulfonyl)-reserpate and 50 ml. of methanol is heated at 100 in a sealed vessel for seven days. The solvent is evaporated, the residue is dissolved as completely as possible in methylene chloride, and the solid material is removed after shaking with a 5 percent aqueous solution of sodium carbonate. The organic solution is washed with saturated aqueous sodium chloride and then evaporated; the residue is taken up in methylene chloride, which solution is passed through a column containing a diatomaceous earth preparation. The column is eluted with methylene chloride and methylene chloride containing 5 percent methanol. The combined eluted product is recrystallized from a mixture of benzene and cyclohexane. The first crystalline crop is discarded, the filtrate is concentrated to yield a small amount of methyl lS-O-methyl-reserpate, M.P. 224228. The slightly impure product is identical with the compound prepared according to the procedure of Example 1.

The starting material may be prepared as follows: To a solution of 4.32 g. of methyl 18-epi-reserpato in 50 ml. of pyridine is added 6.7 g. of 4-brorno-benzene sulfonyl chloride. After Warming to ensure complete solution, the reaction mixture is cooled and allowed to stand for three days and is then poured into ml. of cold Water. The organic material is extracted with methylene chloride, the organic solution is washed with a five percent aqueous solution of sodium carbonate and a saturated sodium chloride solution and evaporated under reduced pressure at a temperature below 50. The residue is washed with acetontrile to yield the methyl l8-epi-O-(4-bromophenyl)-sulfonyl-reserpate, which is purified by recrystallization from acetonitrile, M.P. 2l0-212 (decomposition); [a] =33 (chloroform).

Example 31 To a solution of 0.75 g. of methyl l8-O-methyl-3-dehydroreserpate in a mixture of 8 ml. of tetrahydrofuran, 8 ml. of acetone and 7.2 ml. of water are added 0.8 ml. of concentrated perchloric acid of about 70 percent strength and then 0.7 g. of powdered zinc. The mixture is refluxed while constantly stirring for fifteen minutes under an atmosphere of nitrogen, and then evaporated to dryness under reduced pressure. The oily residue is dissolved in 20 ml. of a 3:2-mixture of acetone and water, the solution is made basic with aqueous ammonia and the organic solvent is evaporated off. 25 ml. of water is added, the organic material is extracted with methylene chloride and the organic solution is dried over sodium sulfate and then evaporated to dryness to leave 0.72 g. of a foamy material.

The residue is chromatographed on 20 g. of alumina (Woelm, neutral, activity II to III). The following fractions are collected and each of the fractionssubjected to paper chromatography in the system chloroform/formamide to determine the identity of the various fractions:

Fraction Solvent Amgunt Rf-value 1 50 m1. of benzene 0.200 0.15(trace). 0.83(trace). 0.90. 2 d0 0.025 glgfirace).

.8 3 50 ml. of methylene chloride 0.160 0.15(trace).

0.83. 0.080 0.83. 0.060 0.83. do 0.010 0.83. 150 ml.0f methylene ch rid 0.160 0.83.

taining 0.5 percent of methanol. ml. of methanol 0.030 0.00 and impurities.

Fractions 2 to 7 inclusive are combined and dissolved in a hot 1:3-mixture of benzene and cyclohexane, and the solution is concentrated until crystalline material is formed. A first crop of 0.35 g. representing methyl l8-O-methyl-reserpate melts at 230-233 and has a rotation of [a] =-l()8. The infrared absorption curve is identical with the one of methyl l8-O-methyl-reserpate prepared according to the procedure described in Example 1. The ultraviolet absorption spectrum in ethanol shows the following characteristic bands (values given in my): X at 226-228 (e=34,350), 270-272 (e=4960) and 296-299 6:6200 rshoulder at 264 @4710); A 252 $3620 and 281-282 :4120

The starting material may be prepared, for example, by treating methyl 3-oXo-2,3-seco-reserpate with diazomethane in the presence of a fluoboric acid preparation prepared according to the procedure described in Example 1 and treating the resulting methyl 18-O-methyl-3-oxo-2,3- seco-reserpate with phosphorus oxychloride. A mixture of the resulting salt in dilute acetic acid is made basic with aqueous ammonia, the yellow precipitate is extracted with methylene chloride, the organic solution is dried over sodium sulfate and evaporated to dryness to yield the desired methyl 18-O-methyl-3-dehydro-reserpate as a foam, which is directly used in the above reaction. A small amount is recrystallized from ethyl acetate, M.P. 201-205"; it has a rotation of [a] =+122i10, and the ultraviolet absorption spectrum shows the following characteristic bands in ethanol (values in ma): kmax, at 255-256 (e=9220), 264-265 (5:9020), 290-295 (e :8990), 317-319 (e=17,100), 330-331 (e=16,980) and 390 (6 4720; A at 221 (e=20,520); Amman at 227-232 (e=l8,770); X at 252 (6 91.30), 260-262 (e=8960), 273-278 (5:7490), 294-295 (e=8900), 324- 325 (e=15,780) and 348 (e=3800), and the following characteristic bands in ethanol, containing a small amount of hydrochloric acid: A at 239 (e=4920), 258-260 (5:6200), and 386-388 $25,480 r at 297- 302 (E=1l70); and )t at 230-232 (6 4860), 242-246 (e=4500) and 280-282 (5:60).

The methyl 18-O-methyl-3-dehydro-reserpate perchlorate may be prepared as follows: To a solution of 0.035 g. of the previously described methyl l8-O-methyl-3-dehydro-reserpate in ml. of a lzl-mixture of methanol and water are added several drops of aqueous perchloric acid of 35 percent strength. The solid material is filtered off and recrystallized from ethanol to yield the methyl 18-O-methyl-3-dehydroreserpate perchlorate, M.P. 149- 154. This salt may be used in the above reduction procedure to form the desired methyl 18-O-methyl-reserpate.

The methyl l8-O-methyl-3-oxo-2,3-seco-reserpate used as the intermediate in the preparation of the starting material may also be obtained, for example, by etherifying in methyl 3 B hydroxy-Za-methoxy-7-oxo-1m,2fi,3m,4,7,8,9a, 10u-octahydro-naphthalene l/i-carboxylate the free hydroxyl group with diazomethane in the presence of fluoboric acid. The resulting methyl 2a,3fi-dimethoxy-7-oxo-la, 2B,3a,4,7,8,9a,10a-octahydro-naphtha1ene lfi-carboxylate is then oxidized first with osmium tetroxide to the methyl 5a,6a-dihydroxy 20:,33 dimethoxy-7-oxo-la,2fi,3a,4,5/8, 6,3,7,8,9a,10a-clecahydro-naphthalene lB-carboxylate and then with periodic acid hydrate to the methyl Sfl-aldehydo- 6,8 carboxymethyl 2a,3[3 dimethoxy 10c,2/5,3o,4,5oz, 6a-hexahydro-benzene lfi-carboxylate, which is then esterified with diazomethane to the methyl 5B-aldehydo-6ficarbomethoxy methyl 2a,3fi-dimethoxy-1a,2fl,3a,4,5a, 6u-hexahydro-benzene LB-carboxylate. The latter is then condensed with G-methoxy-tryptamine in benzene to form the methyl 3-methoxy-18-O-methyl-3-oxo-2,3;3,4-bis-sec- 4(2l)-dehydro-reserpate, which in turn is treated with sodium borohydride to reduce the Schiff-base type double bond. After re-esterification of any hydrolyzed carboxyl groups With diazomethane, the resulting methyl 3-methoxy-l8-O-methyl-3-0X0 2,3 ;3,4 bis seco reserpate is treated with acetic acid anhydride in pyridine to yield the desired methyl 18-O-methyl-3-oxo-2,3-seco-reserpate used as the intermediate in the preparation of the starting material.

Other lower alkyl l8-O-lower alkyl-3-dehydro-reserpates, which may be used in the above procedure for the preparation of the compounds of this invention are, for example,

methyl 18-O-ethyl-3-dehydro-reserpate, methyl 18-O-n-propyl-3-dehydro-reserpate, methyl 18-O-isopropyl-3-dehydro-reserpate, methyl 18-O-n-butyl-3-dehydro-reserpate, ethyl lS-O-methyl-S-dehydro-reserpate, ethyl 18-O-ethyl-3-dehydro-reserpate,

ethyl 18-O-n-propyl-3-dehydro-reserpate, n-propyl 18-O-methyl-3-dehydro-reserpate, n-propyl l8-O-ethy1-3-dehydro-reserpate, isopropyl 18-O-methyl-3-dehydro-reserpate, n-butyl l8-O-methyl-3-dehydro-reserpate, isobutyl l8-O-methyl-3-dehydro-reserpate and the like,

or salts of these compounds, such as the perchlorate and the like.

Other highly useful starting materials are the lower alkyl 18-O-lower alkyl-10-methyoxy-3-dehydrodeserpidates, e.g.

methyl 10-methoxy-l8-O-methyl-3-dehydro-deserpidate,

methyl 18-O-ethyl-10-methoxy-3-dehydro-deserpidate,

methyl IO-methoxy- 1 8-O-n-propyl-3-dehydro-deserpidate,

methyl 1S-O-n-butyl-lO-methoxy-3-dehydro-deserpidate,

ethyl 10-methoxy- 1 8-O-methyl-3-dehydro-deserpidate,

ethyl IO-methoxy-l8-O-n-propyl-3-dehydro-deserpidate,

n-propyl IO-methoxy-18-O-methyl-3-dehydro-deserpidate,

isopropyl 10-methoxy-l8-O-methyl-3-dehydro-deserpidate and the like,

or lower alkyl 18-O-lower alkyl-3-dehydro-deserpidates,

methyl 18-O-methyl-3-dehydro-deserpidate,

methyl 18-O-ethyl-3-dehydro-deserpidate,

methyl l8-O-n-butyl-3 -dehydro-deserpidate,

ethyl 1S-O-methyl-S-dehydro-deserpidate,

ethyl 18-O-n-propyl-3-dehydro-deserpidate,

n-propyl l8-O-methyl-3-dehydro-deserpidate,

isopropyl 18-O-methyl-3-dehydro-deserpidate,

n-butyl 18-O-methyl-3-dehydro-deserpidate, and the like,

or salts thereof, such as the perchlorate and the like,

as well as lower alkyl 18-O-lower alky1-5-methyl-3-dehydroreserpates, e.g.

methyl S-methyl-18-O-methyl-3-dehydro-reserpate,

methyl 18-O-ethyl-5-methyl-3-dehydro-reserpate,

ethyl 5-methyl-18-O-methyl-3-dehydro-reserpate and the like,

lower alkyl 18-O-lower alkyl-6-methyl-3-dehydro-reserpates, e.g.

methyl fi-methyl-l8-O-methyl-3-dehydro-reserpate,

methyl 6-methyl-18-0-n-propyl-3-dehydro-reserpate,

ethyl -methyl-l8-O-methyl-3-dehydro-reserpate and the like,

lower alkyl l8-O-lower alkyl-6-methyl-3-dehydro-deserpidates, e.g.

methyl 6-methyl-l8-O-methyl-3-dehydro-deserpidate,

methyl l8-O-ethyl-6-methyl-3-dehydro-deserpidate,

ethyl 6-methyl-l8-O-methyl-3-dehydro-deserpidate and the like,

lower alkyl 18-O-lower alkyl-9-methyl-3-dehydro-deserpidates, e.g.

methyl 9-methyl-l8-O-methyl-3-dehydro-deserpidate,

methyl 18-O-isopropyl-9-methyl-3-dehydro-deserpidate,

ethyl 9-methyl-18-O-methyl-3-dehydro-deserpidate and the like,

lower alkyl 18-O-lower alkyl-l0-methyl-3-dehydro-deserpidates, e.g.

methyl lO-methyl-18-Omethyl-3-dehydro-deserpidate,

methyl lS-O-ethyl-l0-methyl-3-dehyclro-deserpidate,

ethyl lO-methyl-l8-0-methyl-3-dehydro-deserpidate and the like, 

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA: 